43 results on '"Andrew Hitron"'
Search Results
2. Supplementary Figure 5 from Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo
- Author
-
Xianglin Shi, Jia Luo, Gang Chen, Andrew Hitron, Songze Ding, Xin Wang, Senping Cheng, Young-Ok Son, Zhuo Zhang, Ning Gao, and Amit Budhraja
- Abstract
PDF file - 2.2MB
- Published
- 2023
3. Supplementary Figure 2 from Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo
- Author
-
Xianglin Shi, Jia Luo, Gang Chen, Andrew Hitron, Songze Ding, Xin Wang, Senping Cheng, Young-Ok Son, Zhuo Zhang, Ning Gao, and Amit Budhraja
- Abstract
PDF file - 2.2MB
- Published
- 2023
4. Supplementary Methods, Figure Legends 1-5 from Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo
- Author
-
Xianglin Shi, Jia Luo, Gang Chen, Andrew Hitron, Songze Ding, Xin Wang, Senping Cheng, Young-Ok Son, Zhuo Zhang, Ning Gao, and Amit Budhraja
- Abstract
PDF file - 109K
- Published
- 2023
5. Supplementary Figure 3 from Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo
- Author
-
Xianglin Shi, Jia Luo, Gang Chen, Andrew Hitron, Songze Ding, Xin Wang, Senping Cheng, Young-Ok Son, Zhuo Zhang, Ning Gao, and Amit Budhraja
- Abstract
PDF file - 3.3MB
- Published
- 2023
6. Supplementary Figure 1 from Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo
- Author
-
Xianglin Shi, Jia Luo, Gang Chen, Andrew Hitron, Songze Ding, Xin Wang, Senping Cheng, Young-Ok Son, Zhuo Zhang, Ning Gao, and Amit Budhraja
- Abstract
PDF file - 2.7MB
- Published
- 2023
7. Expression of Concern: 'Cadmium Induces Intracellular Ca2+- and H2O2-Dependent Apoptosis through JNK- and p53-Mediated Pathways in Skin Epidermal Cell line'
- Author
-
Zhuo Zhang, Young-Ok Son, J. Andrew Hitron, Xianglin Shi, Jeong-Chae Lee, and Jingju Pan
- Subjects
inorganic chemicals ,Cadmium ,chemistry ,Apoptosis ,Molecular Toxicology ,chemistry.chemical_element ,Line (text file) ,Toxicology ,Intracellular ,Cell biology - Abstract
Cadmium is a toxic heavy metal and has been widely used in industry. The skin is an important target for this metal. The mechanisms by which cadmium leads to damage to the skin are unclear at present. The aims of this study were to examine whether cadmium induces apoptosis in mouse skin epidermal cell line, JB6 Cl41 cells, and to investigate the cellular mechanisms by which cadmium causes cytotoxicity in the cells. The present study showed that cadmium induced cell death by apoptosis in a dose-dependent manner, as proven by the appearance of cell shrinkage, the increase of Annexin V positively stained cells, and the formation of nuclear DNA ladders. Cadmium-induced apoptosis involved a mitochondria-mediated mechanism but not caspase-dependent pathway in that the critical apoptotic events induced by cadmium, such as the decrease of Bcl-2/Bcl-xL, the increase of GADD45α, and the nuclear translocation of apoptosis inducing factor, were not affected by the inhibition of executive caspases. In contrast, blockage of p53 and JNK by pharmacological inhibitors or small interference RNA transfection suppressed the cadmium-induced apoptosis with the concomitant inhibition of antiapoptotic Bcl-2 family proteins and GADD45α, respectively. Furthermore, the activation of p53 and JNK and their downstream proteins in cadmium-exposed cells were inhibited by individual treatment with catalase and Bapta-acetoxymethyl. These results suggest that cadmium induces apoptosis via the activation of JNK- and p53-mediated signaling, where calcium ion and hydrogen peroxide act as the pivotal mediators of the apoptotic signaling.
- Published
- 2020
8. n-type charge transport in heavily p-doped polymers
- Author
-
Xuyi Luo, Ashkan Abtahi, Jacob L. Hempel, Chad Risko, Douglas R. Strachan, Uma Shantini Ramasamy, Kenneth R. Graham, Zhiming Liang, Hyun Ho Choi, Tuo Liu, Kyle N. Baustert, Armin Ansary, J. Andrew Hitron, Jianguo Mei, Alex M. Boehm, and Vitaly Podzorov
- Subjects
Materials science ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Condensed Matter::Materials Science ,Delocalized electron ,Hall effect ,Condensed Matter::Superconductivity ,Seebeck coefficient ,General Materials Science ,chemistry.chemical_classification ,Dopant ,Mechanical Engineering ,Doping ,technology, industry, and agriculture ,General Chemistry ,Electron acceptor ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,Thermoelectric materials ,0104 chemical sciences ,chemistry ,Mechanics of Materials ,Chemical physics ,Condensed Matter::Strongly Correlated Electrons ,Charge carrier ,0210 nano-technology - Abstract
It is commonly assumed that charge-carrier transport in doped π-conjugated polymers is dominated by one type of charge carrier, either holes or electrons, as determined by the chemistry of the dopant. Here, through Seebeck coefficient and Hall effect measurements, we show that mobile electrons contribute substantially to charge-carrier transport in π-conjugated polymers that are heavily p-doped with strong electron acceptors. Specifically, the Seebeck coefficient of several p-doped polymers changes sign from positive to negative as the concentration of the oxidizing agents FeCl3 or NOBF4 increase, and Hall effect measurements for the same p-doped polymers reveal that electrons become the dominant delocalized charge carriers. Ultraviolet and inverse photoelectron spectroscopy measurements show that doping with oxidizing agents results in elimination of the transport gap at high doping concentrations. This approach of heavy p-type doping is demonstrated to provide a promising route to high-performance n-type organic thermoelectric materials. A broad range of characterization techniques is used to understand the dominant electron conduction in various p-type doped π-conjugated polymers, which show p-type and n-type thermoelectric power factors depending on the dopant concentration.
- Published
- 2019
9. Different roles of ROS and Nrf2 in Cr(VI)-induced inflammatory responses in normal and Cr(VI)-transformed cells
- Author
-
Poyil Pratheeshkumar, Lei Wang, Yong-Ok Son, Sasidharan Padmaja Divya, John Andrew Hitron, Zhuo Zhang, Xianglin Shi, and Ram Vinod Roy
- Subjects
Chromium ,0301 basic medicine ,NF-E2-Related Factor 2 ,Cell ,SOD2 ,Inflammation ,Toxicology ,medicine.disease_cause ,environment and public health ,Article ,Cell Line ,03 medical and health sciences ,medicine ,Humans ,Gene silencing ,Carcinogen ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Tumor Necrosis Factor-alpha ,Chemistry ,respiratory system ,Molecular biology ,Oxidative Stress ,Transformation (genetics) ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Cyclooxygenase 2 ,Immunology ,medicine.symptom ,Reactive Oxygen Species ,Oxidative stress - Abstract
Hexavalent chromium (Cr(VI)) is classified as a human carcinogen. Cr(VI) has been associated with adenocarcinomas and squamous cell carcinoma of the lung. The present study shows that acute Cr(VI) treatment in human bronchial epithelial cells (BEAS-2B) increased inflammatory responses (TNF-α, COX-2, and NF-кB/p65) and expression of Nrf2. Cr(VI)-induced generation of reactive oxygen species (ROS) are responsible for increased inflammation. Despite the fact that Nrf2 is a master regulator of response to oxidative stress, silencing of Nrf2 in the acute Cr(VI) treatment had no effect on Cr(VI)-induced inflammation. In contrast, in Cr(VI)-transformed (CrT) cells, Nrf2 is constitutively activated. Knock-down of this protein resulted in decreased inflammation, while silencing of SOD2 and CAT had no effect in the expression of these inflammatory proteins. Results obtained from the knock-down of Nrf2 in CrT cells are very different from the results obtained in the acute Cr(VI) treatment. In BEAS-2B cells, knock-down of Nrf2 had no effect in the inflammation levels, while in CrT cells a decrease in the expression of inflammation markers was observed. These results indicate that before transformation, ROS plays a critical role while Nrf2 not in Cr(VI)-induced inflammation, whereas after transformation (CrT cells), Nrf2 is constitutively activated and this protein maintains inflammation while ROS not. Constitutively high levels of Nrf2 in CrT binds to the promoter regions of COX-2 and TNF-α, leading to increased inflammation. Collectively, our results demonstrate that before cell transformation ROS are important in Cr(VI)-induced inflammation and after transformation a constitutively high level of Nrf2 is important.
- Published
- 2016
10. Cancer Stem-Like Cells Accumulated in Nickel-Induced Malignant Transformation
- Author
-
Young-Ok Son, Donghern Kim, Xianglin Shi, Poyil Pratheeshkumar, John Andrew Hitron, James T.F. Wise, Lei Wang, Ram Vinod Roy, Zhuo Zhang, Jia Fan, and Jin Dai
- Subjects
Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,Cell ,Population ,Mice, Nude ,Bronchi ,Toxicology ,medicine.disease_cause ,Cell Line ,Malignant transformation ,03 medical and health sciences ,Superoxide Dismutase-1 ,0302 clinical medicine ,Nickel ,Cancer stem cell ,Internal medicine ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Cell Self Renewal ,Role of Cancer Stem-Like Cells in Nickel-Related Malignancies ,education ,education.field_of_study ,Chemistry ,Cancer ,Cell Differentiation ,Epithelial Cells ,Environmental exposure ,medicine.disease ,Cell Transformation, Neoplastic ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research ,Stem cell ,Carcinogenesis - Abstract
Nickel compounds are known as human carcinogens. Chronic environmental exposure to nickel is a worldwide health concern. Although the mechanisms of nickel-induced carcinogenesis are not well understood, recent studies suggest that stem cells/cancer stem cells are likely important targets. This study examines the role of cancer stem cells in nickel-induced cell transformation. The nontransformed human bronchial epithelial cell line (Beas-2B) was chronically exposed to nickel chloride for 12 months to induce cell transformation. Nickel induced Beas-2B cell transformation, and cancer stem-like cells were enriched in nickel-transformed cell (BNiT) population. The BNiT cancer stem-like cells demonstrated enhanced self-renewal and distinctive differentiation properties. In vivo tumorigenesis studies show that BNiT cancer stem-like cells possess a high tumor-initiating capability. It was also demonstrated that superoxide dismutase 1 was involved in the accumulation of cancer stem-like cells; the regulation of superoxide dismutase 1 expression was different in transformed stem-like cells and nontransformed. Overall, the accumulation of stem-like cells and their enhanced stemness functions contribute to nickel-induced tumorigenesis. Our study provides additional insight into the mechanisms by which metals or other chemicals can induce carcinogenesis.
- Published
- 2016
11. Antioncogenic and Oncogenic Properties of Nrf2 in Arsenic-induced Carcinogenesis
- Author
-
Sasidharan Padmaja Divya, Jia Luo, Gang Chen, Ram Vinod Roy, Young-Ok Son, Poyil Pratheeshkumar, Lei Wang, Zhuo Zhang, John Andrew Hitron, Mei Xu, and Xianglin Shi
- Subjects
inorganic chemicals ,chemistry.chemical_classification ,Reactive oxygen species ,Small interfering RNA ,integumentary system ,biology ,Autophagy ,Molecular Bases of Disease ,Cell Biology ,respiratory system ,medicine.disease_cause ,digestive system ,Biochemistry ,Molecular biology ,Cell biology ,Superoxide dismutase ,Small hairpin RNA ,chemistry ,Cell culture ,Apoptosis ,biology.protein ,medicine ,Carcinogenesis ,Molecular Biology - Abstract
Arsenic (As(3+)) is a carcinogen with considerable environmental and occupational relevancy. The present study shows that As(3+)-transformed human lung bronchial epithelial BEAS-2B cells (AsT cells) exhibit the property of apoptosis resistance. The level of basal reactive oxygen species (ROS) is very low in AsT cells in correlation with elevated expressions of both antioxidant enzymes and antiapoptotic proteins. Nuclear factor erythroid 2-related factor (Nrf2) and p62 are constitutively expressed. These two proteins up-regulate antioxidant enzymes and antiapoptotic proteins. The knockdown of Nrf2 or p62 by small interfering RNA (siRNA) enhanced both ROS levels and As(3+)-induced apoptosis in transformed cells. AsT cells have autophagy deficiency as evidenced by reduced formation of microtubule-associated protein 1 light chain 3 (LC3)-II, GFP-LC3 puncta, and autophagy flux. Results obtained using a soft agar assay and shRNA Nrf2-transfected cells show that Nrf2 plays an antioncogenic role before transformation, whereas this transcription factor plays an oncogenic role after transformation. In addition, depletion of Nrf2 by shRNA dramatically inhibited growth and proliferation of transformed cells. Furthermore, the Nrf2 protein levels and antiapoptotic and antioxidant enzyme levels are higher in lung adenocarcinoma than in normal tissues. Collectively, this study demonstrates that a constitutively high level of Nrf2 in AsT cells up-regulates the antioxidant proteins catalase and superoxide dismutase as well as the antiapoptotic proteins Bcl-2 and Bcl-xL. The final consequences are decreased ROS generation and increased apoptotic resistance, cell survival and proliferation, and tumorigenesis.
- Published
- 2015
12. Retraction: 'Ethanol Enhances Tumor Angiogenesis In Vitro Induced by Low-Dose Arsenic in Colon Cancer Cells Through Hypoxia-Inducible Factor 1 Alpha Pathway'
- Author
-
Xin Wang, Jia Luo, John Andrew Hitron, Pratheeshkumar Poyil, Lei Wang, Amit Budhraja, Young-Ok Son, Jeong-Chae Lee, Songze Ding, Zhuo Zhang, Xianglin Shi, and Qinchen Lin
- Subjects
inorganic chemicals ,Vascular Endothelial Growth Factor A ,Cell signaling ,Time Factors ,Arsenites ,Cell Survival ,Neovascularization, Physiologic ,medicine.disease_cause ,Transfection ,Toxicology ,chemistry.chemical_compound ,Genes, Reporter ,Paracrine Communication ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,Protein kinase B ,PI3K/AKT/mTOR pathway ,NADPH oxidase ,integumentary system ,biology ,Dose-Response Relationship, Drug ,Ethanol ,Superoxide Dismutase ,NADPH Oxidases ,Environmental exposure ,Catalase ,HCT116 Cells ,Hypoxia-Inducible Factor 1, alpha Subunit ,Molecular biology ,Sodium Compounds ,Up-Regulation ,Retraction ,Vascular endothelial growth factor ,Enzyme Activation ,Vascular endothelial growth factor A ,chemistry ,Culture Media, Conditioned ,Colonic Neoplasms ,biology.protein ,Cancer research ,Carcinogens ,Phosphatidylinositol 3-Kinase ,Carcinogenesis ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt ,Research Article ,Signal Transduction - Abstract
Health effects due to environmental exposure to arsenic are a major global health concern. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. Ethanol is also a well-established risk factor for many malignancies. However, little is known about the effects of coexposure to arsenic and ethanol in tumor development. In this study, we investigate the signaling and angiogenic effect of coexposure of arsenic and ethanol on different colon cancer cell lines. Results show that ethanol markedly enhanced arsenic-induced tumor angiogenesis in vitro. These responses are related to intracellular reactive oxygen species (ROS) generation, NADPH oxidase activation, and upregulation of PI3K/Akt and hypoxia-inducible factor 1 alpha (HIF-1α) signaling. We have also found that ethanol increases the arsenic-induced expression and secretion of angiogenic signaling molecules such as vascular endothelial growth factor, which further confirmed the above observation. Antioxidant enzymes inhibited arsenic/ethanol-induced tumor angiogenesis, demonstrating that the responsive signaling pathways of coexposure to arsenic and ethanol are related to ROS generation. We conclude that ethanol is able to enhance arsenic-induced tumor angiogenesis in colorectal cancer cells via the HIF-1α pathway. These results indicate that alcohol consumption should be taken into consideration in the investigation of arsenic-induced carcinogenesis in arsenic-exposed populations.
- Published
- 2020
13. Expression of Concern: 'The Dual Roles of c-Jun NH2-Terminal Kinase Signaling in Cr(VI)-Induced Apoptosis in JB6 Cells'
- Author
-
Zhuo Zhang, Nancy Lan Guo, Jeong-Chae Lee, John Andrew Hitron, Xianglin Shi, Young-Ok Son, Amit Budhraja, and Senping Cheng
- Subjects
Apoptosis ,Chemistry ,C jun nh2 terminal kinase ,Signal transduction ,Toxicology ,Phosphotransferases ,Cell biology - Published
- 2020
14. Withdrawal: Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis
- Author
-
Young-Ok Son, Lei Wang, John Andrew Hitron, Xianglin Shi, Poyil Pratheeshkumar, Zhuo Zhang, and Ram Vinod Roy
- Subjects
inorganic chemicals ,Cadmium ,chemistry ,Cancer research ,medicine ,chemistry.chemical_element ,Cell Biology ,Biology ,Carcinogenesis ,medicine.disease_cause ,Molecular Biology ,Biochemistry ,Apoptosis resistance - Abstract
Background: Cadmium-transformed cells have a property of apoptosis resistance.
- Published
- 2018
15. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways
- Author
-
Yitao Wang, Padmaja Asha, Sasidharan Padmaja Divya, Jin Dai, Young-Ok Son, Ram Vinod Roy, Lei Wang, Poyil Pratheeshkumar, Zhuo Zhang, Donghern Kim, John Andrew Hitron, and Xianglin Shi
- Subjects
Chromium ,Lung Neoplasms ,Cell Survival ,Mice, Nude ,Bronchi ,Transfection ,Toxicology ,medicine.disease_cause ,Article ,Cell Line ,Malignant transformation ,Lipid peroxidation ,chemistry.chemical_compound ,medicine ,Animals ,Anticarcinogenic Agents ,Humans ,Angiogenic Proteins ,Luteolin ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,NADPH oxidase ,Dose-Response Relationship, Drug ,biology ,Chemistry ,Epithelial Cells ,Free Radical Scavengers ,Xenograft Model Antitumor Assays ,Molecular biology ,Oxidative Stress ,Cell Transformation, Neoplastic ,Biochemistry ,Cytoprotection ,Cell culture ,biology.protein ,Potassium Dichromate ,Inflammation Mediators ,Apoptosis Regulatory Proteins ,Reactive Oxygen Species ,Oxidative stress ,Signal Transduction - Abstract
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis.
- Published
- 2014
16. Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin
- Author
-
Binoy Joseph, Jian Lu, Young-Ok Son, Lei Wang, John Andrew Hitron, Zhuo Zhang, Yuanqin Yin, Donghern Kim, Poyil Pratheeshkumar, Ram Vinod Roy, Sasidharan Padmaja Divya, Xin Wang, Yitao Wang, and Xianglin Shi
- Subjects
Ultraviolet Rays ,Skin Absorption ,p38 mitogen-activated protein kinases ,Inflammation ,Biology ,Toxicology ,medicine.disease_cause ,Article ,Anthocyanins ,Mice ,Random Allocation ,chemistry.chemical_compound ,Glucosides ,medicine ,Animals ,skin and connective tissue diseases ,Pharmacology ,Mice, Hairless ,Dose-Response Relationship, Drug ,integumentary system ,Kinase ,NF-kappa B ,NF-κB ,medicine.disease ,Hairless ,Oxidative Stress ,IκBα ,chemistry ,Immunology ,Cancer research ,Female ,Mitogen-Activated Protein Kinases ,medicine.symptom ,Skin cancer ,Oxidative stress ,Signal Transduction - Abstract
Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE2 and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2'-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways.
- Published
- 2014
17. Anti-apoptotic proteins and catalase-dependent apoptosis resistance in nickel chloride-transformed human lung epithelial cells
- Author
-
Lei Wang, Jian Lu, Andrew Hitron, Shuang Yin Han, Li Juan Sun, Xin Wang, Yuan Qin Yin, Poyil Pratheeshkumar, Song Ze Ding, Yan Rui Zhang, Xiuling Li, Amit Budhraja, and Yu Xiu Yang
- Subjects
tumor ,Cancer Research ,Programmed cell death ,Lung Neoplasms ,Cell ,bcl-X Protein ,Bcl-xL ,Biology ,medicine.disease_cause ,nickel ,03 medical and health sciences ,0302 clinical medicine ,BEAS-2B cell ,medicine ,oxidative stress ,Humans ,Bcl-2 ,RNA, Small Interfering ,Protein kinase B ,030304 developmental biology ,0303 health sciences ,Oncogene ,apoptosis ,Epithelial Cells ,Articles ,Cell cycle ,Catalase ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,lung cancer ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,biology.protein ,Carcinogenesis ,carcinogenesis - Abstract
Chronic exposure to nickel compounds is associated with increased incidence of certain types of human cancer, including lung and nasal cancers. Despite intensive investigation, the oncogenic processes remain poorly understood. Apoptosis resistance is a key feature for tumor cells to escape physiological surveillance and acquire growth advantage over normal cells. Although NiCl2 exposure induces transformation of human lung epithelial cells, little information is available with regard to its molecular mechanisms, it is also not clear if the transformed cells are apoptosis resistant and tumorigenic. We explored the apoptosis resistance properties of nickel chloride‑transformed human lung epithelial cells and the underlying mechanisms. The results showed that transformed BEAS-2B human lung epithelial cells are resistant to NiCl2-induced apoptosis. They have increased Bcl-2, Bcl-xL and catalase protein levels over the passage matched non‑transformed counterparts. The mechanisms of apoptosis resistance are mitochondria‑mediated and caspase-dependent. Forced overexpression of Bcl-2, Bcl-xL and catalase proteins reduced NiCl2-induced cell death; siRNA‑mediated knockdown of their expression sensitized the cells to nickel-induced apoptosis, suggesting that Bcl-2, Bcl-xl and catalase protein expression plays a critical role in apoptosis resistance. Akt also participates in this process, as its overexpression increases Bcl-xL protein expression levels and attenuates NiCl2-induced apoptosis. Furthermore, transformed cells are tumorigenic in a xenograft model. Together, these results demonstrate that nickel-transformed cells are apoptosis‑resistant and tumorigenic. Increased expression of Bcl-2, Bcl-xL and catalase proteins are important mechanisms contributing to transformed cell oncogenic properties.
- Published
- 2013
18. Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets
- Author
-
Songze Ding, Jeong-Chae Lee, Kim Hyun-Jung, Andrew Hitron, Chakkenchath Sreekala, Young-Ok Son, Xin Wang, Amit Budhraja, Lei Wang, Poyil Pratheeshkumar, Xianglin Shi, and Zhuo Zhang
- Subjects
Cancer Research ,Antioxidant ,medicine.medical_treatment ,Apoptosis ,Biology ,Pharmacology ,medicine.disease_cause ,Chemoprevention ,Article ,Neoplasms ,Drug Discovery ,medicine ,Animals ,Anticarcinogenic Agents ,Humans ,Carcinogen ,Biological Products ,Cancer prevention ,Neovascularization, Pathologic ,Drug discovery ,Cancer ,medicine.disease ,Clinical trial ,Molecular Medicine ,Signal transduction ,Carcinogenesis - Abstract
Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions.
- Published
- 2012
19. Quercetin inhibits Cr(VI)-induced malignant cell transformation by targeting miR-21-PDCD4 signaling pathway
- Author
-
Ram Vinod Roy, Lilia Turcios, Xianglin Shi, Padmaja Asha, Jin Dai, Young-Ok Son, Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Donghern Kim, John Andrew Hitron, Zhuo Zhang, and Lei Wang
- Subjects
0301 basic medicine ,Programmed cell death ,Tumor suppressor gene ,medicine.disease_cause ,Malignant transformation ,quercetin ,miR-21-PDCD4 signaling ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Carcinogen ,hexavalent chromium ,malignant cell transformation ,ROS ,Oncomir ,3. Good health ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Signal transduction ,Quercetin ,Carcinogenesis ,Research Paper - Abstract
// Poyil Pratheeshkumar 1, 2, * , Young-Ok Son 1, 2, * , Sasidharan Padmaja Divya 1, 2 , Lei Wang 1, 2 , Lilia Turcios 3 , Ram Vinod Roy 1, 2 , John Andrew Hitron 1, 2 , Donghern Kim 2 , Jin Dai 2 , Padmaja Asha 4 , Zhuo Zhang 2 , Xianglin Shi 1, 2 1 Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA 2 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA 3 Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY, USA 4 National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India * These authors have contributed equally to this work Correspondence to: Xianglin Shi, email: xshi5@email.uky.edu Keywords: hexavalent chromium, quercetin, ROS, malignant cell transformation, miR-21-PDCD4 signaling Received: April 16, 2016 Accepted: June 03, 2016 Published: June 17, 2016 ABSTRACT Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Inhibition of Cr(VI)-induced carcinogenesis by a dietary antioxidant is a novel approach. Quercetin is one of the most abundant dietary flavonoids widely present in many fruits and vegetables, possesses potent antioxidant and anticancer properties. MicroRNA-21 (miR-21) is a key oncomiR significantly elevated in the majority of human cancers that exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the effect of quercetin on the inhibition of Cr(VI)-induced malignant cell transformation and the role of miR-21-PDCD4 signaling involved. Our results showed that quercetin decreased ROS generation induced by Cr(VI) exposure in BEAS-2B cells. Chronic Cr(VI) exposure induced malignant cell transformation, increased miR-21 expression and caused inhibition of PDCD4, which were significantly inhibited by the treatment of quercetin in a dose dependent manner. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of quercetin showed reduced tumor incidence compared to Cr(VI) alone treated group. Stable knockdown of miR-21 and overexpression of PDCD4 or catalase in BEAS-2B cells suppressed Cr(VI)-induced malignant transformation and tumorigenesis. Taken together, these results demonstrate that quercetin is able to protect BEAS-2B cells from Cr(VI)-induced carcinogenesis by targeting miR-21-PDCD4 signaling.
- Published
- 2016
20. Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling
- Author
-
John Andrew Hitron, Xianglin Shi, Padmaja Asha, Donghern Kim, Lilia Turcios, Sasidharan Padmaja Divya, Jin Dai, Lei Wang, Ram Vinod Roy, Poyil Pratheeshkumar, Young-Ok Son, and Zhuo Zhang
- Subjects
0301 basic medicine ,Chromium ,Lung Neoplasms ,Tumor suppressor gene ,Cell ,Mice, Nude ,Bronchi ,Respiratory Mucosa ,medicine.disease_cause ,Malignant transformation ,miR-21-PDCD4 signaling ,STAT3 ,03 medical and health sciences ,Mice ,medicine ,Animals ,Humans ,Cells, Cultured ,hexavalent chromium ,A549 cell ,Gene knockdown ,Mice, Inbred BALB C ,IL-6 ,biology ,Chemistry ,RNA-Binding Proteins ,Epithelial Cells ,ROS ,3. Good health ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Oncology ,A549 Cells ,Immunology ,Cancer research ,biology.protein ,Female ,Signal transduction ,Carcinogenesis ,Apoptosis Regulatory Proteins ,Reactive Oxygen Species ,Signal Transduction ,Research Paper - Abstract
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the role of miR-21-PDCD4 signaling in Cr(VI)-induced cell transformation and tumorigenesis. Results showed that Cr(VI) induces ROS generation in human bronchial epithelial (BEAS-2B) cells. Chronic exposure to Cr(VI) is able to cause malignant transformation in BEAS-2B cells. Cr(VI) caused a significant increase of miR-21 expression associated with an inhibition of PDCD4 expression. Notably, STAT3 transcriptional activation by IL-6 is crucial for the Cr(VI)-induced miR-21 elevation. Stable knockdown of miR-21 or overexpression of PDCD4 in BEAS-2B cells significantly reduced the Cr(VI)-induced cell transformation. Furthermore, the Cr(VI) induced inhibition of PDCD4 suppressed downstream E-cadherin protein expression, but promoted β-catenin/TCF-dependent transcription of uPAR and c-Myc. We also found an increased miR-21 level and decreased PDCD4 expression in xenograft tumors generated with chronic Cr(VI)-exposed BEAS-2B cells. In addition, stable knockdown of miR-21 and overexpression of PDCD4 reduced the tumorogenicity of chronic Cr(VI)-exposed BEAS-2B cells in nude mice. Taken together, these results demonstrate that the miR-21-PDCD4 signaling axis plays an important role in Cr(VI)-induced carcinogenesis.
- Published
- 2016
21. Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo
- Author
-
Senping Cheng, Ning Gao, Amit Budhraja, Xin Wang, Jia Luo, Gang Chen, Songze Ding, Xianglin Shi, Young-Ok Son, Zhuo Zhang, and Andrew Hitron
- Subjects
Cancer Research ,Morpholines ,Down-Regulation ,Mice, Nude ,Apoptosis ,Jurkat cells ,Article ,Jurkat Cells ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Apigenin ,RNA, Small Interfering ,Protein kinase B ,Caspase ,Leukemia ,biology ,Cytochrome c ,JNK Mitogen-Activated Protein Kinases ,Cytochromes c ,U937 Cells ,medicine.disease ,Xenograft Model Antitumor Assays ,Mitochondria ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,chemistry ,Chromones ,Caspases ,biology.protein ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,RNA Interference ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
In this study, we investigated the functional role of Akt and c-jun-NH2-kinase (JNK) signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo. Apigenin induced apoptosis by inactivation of Akt with a concomitant activation of JNK, Mcl-1 and Bcl-2 downregulation, cytochrome c release from mitochondria, and activation of caspases. Constitutively active myristolated Akt prevented apigenin-induced JNK, caspase activation, and apoptosis. Conversely, LY294002 and a dominant-negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. Interruption of the JNK pathway showed marked reduction in apigenin-induced caspase activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin resulted in attenuation of tumor growth in U937 xenografts accompanied by inactivation of Akt and activation of JNK. Attenuation of tumor growth in U937 xenografts by apigenin raises the possibility that apigenin may have clinical implications and can be further tested for incorporating in leukemia treatment regimens. Mol Cancer Ther; 11(1); 132–42. ©2011 AACR.
- Published
- 2012
22. Withdrawal: Antioncogenic and oncogenic properties of Nrf2 in arsenic-induced carcinogenesis
- Author
-
Young-Ok Son, Jia Luo, Gang Chen, Xianglin Shi, John Andrew Hitron, Poyil Pratheeshkumar, Lei Wang, Sasidharan Padmaja Divya, Mei Xu, Ram Vinod Roy, and Zhuo Zhang
- Subjects
Carcinogenesis ,Cell Survival ,NF-E2-Related Factor 2 ,bcl-X Protein ,chemistry.chemical_element ,Apoptosis ,medicine.disease_cause ,Models, Biological ,Biochemistry ,Antioxidants ,Arsenic ,Cell Line ,Autophagy ,medicine ,Humans ,Genes, Tumor Suppressor ,Withdrawals/Retractions ,Promoter Regions, Genetic ,Molecular Biology ,Superoxide Dismutase ,business.industry ,RNA-Binding Proteins ,Oncogenes ,Cell Biology ,Catalase ,Cell Transformation, Neoplastic ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Gene Knockdown Techniques ,Cancer research ,Reactive Oxygen Species ,business - Abstract
Arsenic (As(3+)) is a carcinogen with considerable environmental and occupational relevancy. The present study shows that As(3+)-transformed human lung bronchial epithelial BEAS-2B cells (AsT cells) exhibit the property of apoptosis resistance. The level of basal reactive oxygen species (ROS) is very low in AsT cells in correlation with elevated expressions of both antioxidant enzymes and antiapoptotic proteins. Nuclear factor erythroid 2-related factor (Nrf2) and p62 are constitutively expressed. These two proteins up-regulate antioxidant enzymes and antiapoptotic proteins. The knockdown of Nrf2 or p62 by small interfering RNA (siRNA) enhanced both ROS levels and As(3+)-induced apoptosis in transformed cells. AsT cells have autophagy deficiency as evidenced by reduced formation of microtubule-associated protein 1 light chain 3 (LC3)-II, GFP-LC3 puncta, and autophagy flux. Results obtained using a soft agar assay and shRNA Nrf2-transfected cells show that Nrf2 plays an antioncogenic role before transformation, whereas this transcription factor plays an oncogenic role after transformation. In addition, depletion of Nrf2 by shRNA dramatically inhibited growth and proliferation of transformed cells. Furthermore, the Nrf2 protein levels and antiapoptotic and antioxidant enzyme levels are higher in lung adenocarcinoma than in normal tissues. Collectively, this study demonstrates that a constitutively high level of Nrf2 in AsT cells up-regulates the antioxidant proteins catalase and superoxide dismutase as well as the antiapoptotic proteins Bcl-2 and Bcl-xL. The final consequences are decreased ROS generation and increased apoptotic resistance, cell survival and proliferation, and tumorigenesis.
- Published
- 2018
23. Differential sensitivity of CYP1A to 3,3′,4′,4-tetrachlorobiphenyl and benzo(a)pyrene in two Lepomis species
- Author
-
David J. Price, Adria A. Elskus, Eleana Harmel-Laws, Wesley J. Birge, J. Andrew Hitron, and Ben F. Brammell
- Subjects
animal structures ,Physiology ,Health, Toxicology and Mutagenesis ,Toxicology ,Biochemistry ,Lepomis ,chemistry.chemical_compound ,Biomonitoring ,Benzo(a)pyrene ,Cytochrome P-450 CYP1A1 ,Animals ,Pollutant ,Longear sunfish ,Dose-Response Relationship, Drug ,biology ,Cell Biology ,General Medicine ,biology.organism_classification ,Polychlorinated Biphenyls ,Perciformes ,chemistry ,Environmental chemistry ,embryonic structures ,Benzopyrene ,Pyrene ,Water Pollutants, Chemical ,Corn oil ,Environmental Monitoring - Abstract
Although Lepomis species are abundant in a wide variety of habitats throughout North America and could serve as potentially valuable biomonitoring tools, few studies have examined the induction of pollutant biomarkers in this genus. We hypothesized that the induction of cytochrome P-450 1A (CYP1A), a sensitive and widely used indicator of response to aquatic contaminants, would serve as an effective biomarker of organic pollutant exposure in Lepomis species. We examined the response of CYP1A and two of the major pollutant-responsive phase II enzymes, glutathione S-transferase (GST), and uridine diphosphate glucuronyltransferase (UDPGT), in Lepomis exposed to organic pollutants under laboratory and field conditions. Two Lepomis species (longear sunfish, Lepomis megalottis and bluegill, Lepomis macrochirus) were exposed in the laboratory via intraperitoneal injection to corn oil (vehicle), benzo(a)pyrene (BaP) (10 and 50 mg/kg), a polynuclear aromatic hydrocarbon (PAH) or 3,4,3′,4′-tetrachlorobiphenyl (PCB 77) (0.1 and 1.0 mg/kg), a dioxin-like planar halogenated aromatic hydrocarbon (HAH), and sacrificed 2 (BaP) or 7 (corn oil, PCB77) days later. Lepomis hepatic CYP1A exhibited differential sensitivity to these two classes of environmental contaminants. CYP1A activity was weakly induced in bluegill exposed to 1.0 mg/kg PCB 77 (3 fold induction over controls) but strongly induced in both bluegill and longear sunfish exposed to 50 mg/kg BaP (37 and 15 fold induction over controls, respectively). In contrast, hepatic GST activity in both species remained unchanged following the treatment with either compound and hepatic UDPGT activity, which was assessed only in BaP-treated longear sunfish, was unaffected by that chemical, indicating these phase II enzymes may not be sensitive pollutant biomarkers in this genus. Further, longear sunfish collected from a PCB contaminated site displayed relatively low levels of CYP1A activity despite PCB body burdens associated with strong induction of CYP1A activity in other fish species. The strong induction of CYP1A by BaP with much weaker CYP1A response to PCB indicates that CYP1A in Lepomis sp. could be an excellent biomarker for PAH pollution, but may not be a reliable indicator of site contamination by halogenated hydrocarbons. We conclude that Lepomis species provide a useful model for examining the regulation and potential consequences of differential pollutant sensitivity, but that CYP1A in these species should be used with caution as an indicator of halogenated contaminants.
- Published
- 2010
24. Cadmium Induces Intracellular Ca2+- and H2O2-Dependent Apoptosis through JNK- and p53-Mediated Pathways in Skin Epidermal Cell line
- Author
-
Xianglin Shi, J. Andrew Hitron, Zhuo Zhang, Young-Ok Son, Jingju Pan, and Jeong-Chae Lee
- Subjects
Expression of Concern ,inorganic chemicals ,Programmed cell death ,bcl-X Protein ,Apoptosis ,Cell Cycle Proteins ,Cadmium chloride ,Transfection ,Toxicology ,Antioxidants ,Cell Line ,Mice ,chemistry.chemical_compound ,Cadmium Chloride ,Annexin ,Animals ,Phosphorylation ,Protein Kinase Inhibitors ,Caspase ,Dose-Response Relationship, Drug ,biology ,JNK Mitogen-Activated Protein Kinases ,Apoptosis Inducing Factor ,Nuclear Proteins ,Hydrogen Peroxide ,Molecular biology ,Mitochondria ,Cell biology ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Caspases ,biology.protein ,Apoptosis-inducing factor ,Calcium ,RNA Interference ,Epidermis ,Tumor Suppressor Protein p53 ,Signal transduction ,Signal Transduction - Abstract
Cadmium is a toxic heavy metal and has been widely used in industry. The skin is an important target for this metal. The mechanisms by which cadmium leads to damage to the skin are unclear at present. The aims of this study were to examine whether cadmium induces apoptosis in mouse skin epidermal cell line, JB6 Cl41 cells, and to investigate the cellular mechanisms by which cadmium causes cytotoxicity in the cells. The present study showed that cadmium induced cell death by apoptosis in a dose-dependent manner, as proven by the appearance of cell shrinkage, the increase of Annexin V positively stained cells, and the formation of nuclear DNA ladders. Cadmium-induced apoptosis involved a mitochondria-mediated mechanism but not caspase-dependent pathway in that the critical apoptotic events induced by cadmium, such as the decrease of Bcl-2/Bcl-xL, the increase of GADD45alpha, and the nuclear translocation of apoptosis inducing factor, were not affected by the inhibition of executive caspases. In contrast, blockage of p53 and JNK by pharmacological inhibitors or small interference RNA transfection suppressed the cadmium-induced apoptosis with the concomitant inhibition of antiapoptotic Bcl-2 family proteins and GADD45alpha, respectively. Furthermore, the activation of p53 and JNK and their downstream proteins in cadmium-exposed cells were inhibited by individual treatment with catalase and Bapta-acetoxymethyl. These results suggest that cadmium induces apoptosis via the activation of JNK- and p53-mediated signaling, where calcium ion and hydrogen peroxide act as the pivotal mediators of the apoptotic signaling.
- Published
- 2009
25. Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-κB signalings in colorectal cancer cells
- Author
-
Ram Vinod Roy, Jin Dai, Young-Ok Son, Xianglin Shi, Mei Xu, Zhuo Zhang, Poyil Pratheeshkumar, Jia Luo, Lei Wang, John Andrew Hitron, Donghern Kim, and James T.F. Wise
- Subjects
inorganic chemicals ,Male ,Alcohol Drinking ,Arsenites ,chemistry.chemical_element ,Toxicology ,medicine.disease_cause ,Risk Assessment ,Article ,chemistry.chemical_compound ,medicine ,Humans ,Protein kinase B ,Carcinogen ,Arsenic ,Pharmacology ,integumentary system ,Dose-Response Relationship, Drug ,Ethanol ,NFATC Transcription Factors ,Chemistry ,NF-kappa B ,NFAT ,NF-κB ,HCT116 Cells ,Sodium Compounds ,Carcinogens, Environmental ,Oxidative Stress ,Biochemistry ,Cyclooxygenase 2 ,Enzyme Induction ,Cancer research ,Signal transduction ,Carcinogenesis ,Colorectal Neoplasms ,Reactive Oxygen Species ,HT29 Cells ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Arsenic is a known carcinogen to humans, and chronic exposure to environmental arsenic is a worldwide health concern. As a dietary factor, ethanol carries a well-established risk for malignancies, but the effects of co-exposure to arsenic and ethanol on tumor development are not well understood. In the present study, we hypothesized that ethanol would enhance the function of an environmental carcinogen such as arsenic through increase in COX-2 expression. Our in vitro results show that ethanol enhanced arsenic-induced COX-2 expression. We also show that the increased COX-2 expression associates with intracellular ROS generation, up-regulated AKT signaling, with activation of both NFAT and NF-κB pathways. We demonstrate that antioxidant enzymes have an inhibitory effect on arsenic/ethanol-induced COX-2 expression, indicating that the responsive signaling pathways from co-exposure to arsenic and ethanol relate to ROS generation. In vivo results also show that co-exposure to arsenic and ethanol increased COX-2 expression in mice. We conclude that ethanol enhances arsenic-induced COX-2 expression in colorectal cancer cells via both the NFAT and NF-κB pathways. These results imply that, as a common dietary factor, ethanol ingestion may be a compounding risk factor for arsenic-induced carcinogenesis/cancer development.
- Published
- 2015
26. Arsenic Induces Insulin Resistance in Mouse Adipocytes and Myotubes Via Oxidative Stress-Regulated Mitochondrial Sirt3-FOXO3a Signaling Pathway
- Author
-
Bin Huang, Jia Luo, Young-Ok Son, Jin Dai, Ram Vinod Roy, Lei Wang, Zhuo Zhang, Poyil Pratheeshkumar, Mei Xu, John Andrew Hitron, Donghern Kim, Sasidharan Padmaja Divya, and Padmaja Asha
- Subjects
medicine.medical_specialty ,SIRT3 ,Muscle Fibers, Skeletal ,Mitochondrion ,Biology ,Toxicology ,medicine.disease_cause ,Arsenic ,Mice ,Superoxides ,Internal medicine ,Sirtuin 3 ,medicine ,Adipocytes ,Animals ,chemistry.chemical_classification ,Reactive oxygen species ,Arsenic toxicity ,Superoxide Dismutase ,Forkhead Box Protein O3 ,Glucose transporter ,Forkhead Transcription Factors ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Mitochondria ,Oxidative Stress ,Endocrinology ,chemistry ,FOXO3 ,biology.protein ,Insulin Resistance ,Oxidative stress ,GLUT4 ,Signal Transduction ,Transcription Factors - Abstract
Chronic exposure to arsenic via drinking water is associated with an increased risk for development of type 2 diabetes mellitus (T2DM). This study investigates the role of mitochondrial oxidative stress protein Sirtuin 3 (Sirt3) and its targeting proteins in chronic arsenic-induced T2DM in mouse adipocytes and myotubes. The results show that chronic arsenic exposure significantly decreased insulin-stimulated glucose uptake (ISGU) in correlation with reduced expression of insulin-regulated glucose transporter type 4 (Glut4). Expression of Sirt3, a mitochondrial deacetylase, was dramatically decreased along with its associated transcription factor, forkhead box O3 (FOXO3a) upon arsenic exposure. A decrease in mitochondrial membrane potential (Dwm) was observed in both 3T3L1 adipocytes and C2C12 myotubes treated by arsenic. Reduced FOXO3a activity by arsenic exhibited a decreased binding affinity to the promoters of both manganese superoxide dismutase (MnSOD) and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1a, a broad and powerful regulator of reactive oxygen species (ROS) metabolism. Forced expression of Sirt3 or MnSOD in mouse myotubes elevated Dwm and restored ISGU inhibited by arsenic exposure. Our results suggest that Sirt3/FOXO3a/MnSOD signaling plays a significant role in the inhibition of ISGU induced by chronic arsenic exposure.
- Published
- 2015
27. Epigenetic targets of arsenic: emphasis on epigenetic modifications during carcinogenesis
- Author
-
Xianglin Shi, Ram Vinod Roy, Rakesh D, Zhuo Zhang, Lei Wang, Poyil Pratheeshkumar, John Andrew Hitron, Young-Ok Son, Yuanqin Yin, Donghern Kim, and Sasidharan Padmaja Divya
- Subjects
Epigenetic regulation of neurogenesis ,Carcinogenesis ,Health, Toxicology and Mutagenesis ,Biology ,Toxicology ,Chromatin remodeling ,Pathology and Forensic Medicine ,Arsenic ,Epigenesis, Genetic ,Histones ,Mice ,Epigenome editing ,Animals ,Humans ,Cancer epigenetics ,Epigenetics ,Promoter Regions, Genetic ,Epigenomics ,Genetics ,General Medicine ,Epigenome ,DNA Methylation ,Chromatin ,Cell biology ,MicroRNAs ,sense organs - Abstract
DNA methylation and histone modification promote opening and closure of chromatin structure, which affects gene expression without altering the DNA sequence. Epigenetic markers regulate the dynamic nature of chromatin structure at different levels: DNA, histone, noncoding RNAs, as well as the higher-order chromatin structure. Accumulating evidence strongly suggests that arsenic-induced carcinogenesis involves frequent changes in the epigenetic marker. However, progress in identifying arsenic-induced epigenetic changes has already been made using genome-wide approaches; the biological significance of these epigenetic changes remains unknown. Moreover, arsenic-induced changes in the chromatin state alter gene expression through the epigenetic mechanism. The current review provides a summary of recent literature regarding epigenetic changes caused by arsenic in carcinogenesis. We highlight the transgenerational studies needed to explicate the biological significance and toxicity of arsenic over a broad spectrum.
- Published
- 2015
28. Blackberry extract inhibits UVB-induced oxidative damage and inflammation through MAP kinases and NF-κB signalling pathways in SKH-1 mice skin
- Author
-
Sasidharan Padmaja Divya, Xin Wang, Jin Dai, Lei Wang, John Andrew Hitron, Zhuo Zhang, Poyil Pratheeshkumar, Young-Ok Son, Xianglin Shi, Padmaja Asha, Donghern Kim, and Ram Vinod Roy
- Subjects
Neoplasms, Radiation-Induced ,Skin Neoplasms ,Time Factors ,Anti-Inflammatory Agents ,Sunburn ,Cell Cycle Proteins ,Toxicology ,medicine.disease_cause ,Antioxidants ,chemistry.chemical_compound ,Phosphorylation ,skin and connective tissue diseases ,Skin ,biology ,integumentary system ,Chemistry ,NF-kappa B ,Myeloperoxidase ,Female ,medicine.symptom ,Inflammation Mediators ,Mitogen-Activated Protein Kinases ,Signal Transduction ,Ultraviolet Rays ,p38 mitogen-activated protein kinases ,Active Transport, Cell Nucleus ,Inflammation ,digestive system ,Article ,medicine ,Animals ,Cell Proliferation ,Pharmacology ,Mice, Hairless ,Plants, Medicinal ,Dose-Response Relationship, Drug ,Plant Extracts ,NF-κB ,medicine.disease ,Molecular biology ,Hairless ,IκBα ,Disease Models, Animal ,Oxidative Stress ,Fruit ,Immunology ,biology.protein ,Lipid Peroxidation ,Skin cancer ,Rubus ,Sunscreening Agents ,Oxidative stress ,Biomarkers ,DNA Damage ,Phytotherapy - Abstract
Extensive exposure of solar ultraviolet-B (UVB) radiation to skin induces oxidative stress and inflammation that play a crucial role in the induction of skin cancer. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. In this study, we investigated whether blackberry extract (BBE) reduces chronic inflammatory responses induced by UVB irradiation in SKH-1 hairless mice skin. Mice were exposed to UVB radiation (100 mJ/cm 2 ) on alternate days for 10 weeks, and BBE (10% and 20%) was applied topically a day before UVB exposure. Our results show that BBE suppressed UVB-induced hyperplasia and reduced infiltration of inflammatory cells in the SKH-1 hairless mice skin. BBE treatment reduced glutathione (GSH) depletion, lipid peroxidation (LPO), and myeloperoxidase (MPO) in mouse skin by chronic UVB exposure. BBE significantly decreased the level of pro-inflammatory cytokines IL-6 and TNF-α in UVB-exposed skin. Likewise, UVB-induced inflammatory responses were diminished by BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E 2 (PGE 2 ), and inducible nitric oxide synthase (iNOS) levels in UVB-exposed skin. Treatment with BBE inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mouse skin. Immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), cyclobutane pyrimidine dimers (CPD), proliferating cell nuclear antigen (PCNA), and cyclin D1 in UVB-exposed skin. Collectively, these data indicate that BBE protects from UVB-induced oxidative damage and inflammation by modulating MAP kinase and NF-κB signaling pathways.
- Published
- 2015
29. Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis
- Author
-
Poyil Pratheeshkumar, Xianglin Shi, Young-Ok Son, Lei Wang, Ram Vinod Roy, John Andrew Hitron, and Zhuo Zhang
- Subjects
Male ,Lung Neoplasms ,NF-E2-Related Factor 2 ,Green Fluorescent Proteins ,bcl-X Protein ,Mice, Nude ,Apoptosis ,Bronchi ,medicine.disease_cause ,Biochemistry ,Cell Line ,Superoxide dismutase ,Mice ,Genes, Reporter ,medicine ,Autophagy ,Animals ,Humans ,RNA, Small Interfering ,Withdrawals/Retractions ,Molecular Biology ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Superoxide Dismutase ,RNA-Binding Proteins ,Epithelial Cells ,Cell Biology ,Transfection ,Catalase ,Molecular biology ,Cell biology ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,Cell culture ,biology.protein ,Signal transduction ,Carcinogenesis ,Reactive Oxygen Species ,Microtubule-Associated Proteins ,Neoplasm Transplantation ,Cadmium ,Signal Transduction - Abstract
The cadmium-transformed human lung bronchial epithelial BEAS-2B cells exhibit a property of apoptosis resistance as compared with normal non-transformed BEAS-2B cells. The level of basal reactive oxygen species (ROS) is extremely low in transformed cells in correlation with elevated expressions of both antioxidant enzymes (catalase, SOD1, and SOD2) and antiapoptotic proteins (Bcl-2/Bcl-xL). Moreover, Nrf2 and p62 are highly expressed in these transformed cells. The knockdown of Nrf2 or p62 by siRNA enhances ROS levels and cadmium-induced apoptosis. The binding activities of Nrf2 on the antioxidant response element promoter regions of p62/Bcl-2/Bcl-xL were dramatically increased in the cadmium-exposed transformed cells. Cadmium exposure increased the formation of LC3-II and the frequency of GFP-LC3 punctal cells in non-transformed BEAS-2B cells, whereas these increases are not shown in transformed cells, an indication of autophagy deficiency of transformed cells. Furthermore, the expression levels of Nrf2 and p62 are dramatically increased during chronic long term exposure to cadmium in the BEAS-2B cells as well as antiapoptotic proteins and antioxidant enzymes. These proteins are overexpressed in the tumor tissues derived from xenograft mouse models. Moreover, the colony growth is significantly attenuated in the transformed cells by siRNA transfection specific for Nrf2 or p62. Taken together, this study demonstrates that cadmium-transformed cells have acquired autophagy deficiency, leading to constitutive p62 and Nrf2 overexpression. These overexpressions up-regulate the antioxidant proteins catalase and SOD and the antiapoptotic proteins Bcl-2 and Bcl-xL. The final consequences are decrease in ROS generation, apoptotic resistance, and increased cell survival, proliferation, and tumorigenesis.
- Published
- 2014
30. Epithelial-Mesenchymal Transition During Oncogenic Transformation Induced by Hexavalent Chromium Involves Reactive Oxygen Species-Dependent Mechanisms in Lung Epithelial Cells
- Author
-
Yu-Xiu Yang, Xin Wang, Songze Ding, Amit Budhraja, Shuangyin Han, Audrey Michelli-Rivera, Lei Wang, Xiuling Li, Poyil Pratheeshkumar, Yuanqin Yin, Andrew Hitron, and Jian Lu
- Subjects
Chromium ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,DNA damage ,Cell ,Vimentin ,Respiratory Mucosa ,Toxicology ,Article ,Malignant transformation ,Antigens, CD ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Epithelial–mesenchymal transition ,RNA, Messenger ,Cell Shape ,Cell Proliferation ,Pharmacology ,Matrigel ,biology ,Dose-Response Relationship, Drug ,Cell growth ,Epithelial Cells ,Cadherins ,Catalase ,Molecular biology ,Carcinogens, Environmental ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Cell culture ,biology.protein ,Cancer research ,Snail Family Transcription Factors ,Reactive Oxygen Species ,Signal Transduction ,Transcription Factors - Abstract
Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Exposure to Cr(VI) induces DNA damage, cell morphological change and malignant transformation in human lung epithelial cells. Despite extensive studies, the molecular mechanisms remain elusive, it is also not known if Cr(VI)-induced transformation might accompany with invasive properties to facilitate metastasis. We aimed to study Cr(VI)-induced epithelial-mesenchymal transition (EMT) and invasion during oncogenic transformation in lung epithelial cells. The results showed that Cr(VI) at low doses represses E-cadherin mRNA and protein expression, enhances mesenchymal marker vimentin expression and transforms the epithelial cell into fibroblastoid morphology. Cr(VI) also increases cell invasion and promotes colony formation. Further studies indicated that Cr(VI) uses multiple mechanisms to repress E-cadherin expression, including activation of E-cadherin repressors such as Slug, ZEB1, KLF8 and enhancement the binding of HDAC1 in E-cadherin gene promoter, but DNA methylation is not responsible for the loss of E-cadherin. Catalase reduces Cr(VI)-induced E-cadherin and vimentin protein expression, attenuates cell invasion in matrigel and colony formation on soft agar. These results demonstrate that exposure to a common human carcinogen, Cr(VI), induces EMT and invasion during oncogenic transformation in lung epithelial cells and implicate in cancer metastasis and prevention.
- Published
- 2013
31. Quercitrin protects skin from UVB-induced oxidative damage
- Author
-
Wenqi Li, Xin Wang, Ning Gao, Jia Luo, Young-Ok Son, Andrew Hitron, Jian Lu, Poyil Pratheeshkumar, Zhuo Zhang, Lijuan Sun, Xianglin Shi, Yuanqin Yin, Donghern Kim, Lei Wang, and Hua Yao
- Subjects
DNA Repair ,DNA damage ,Ultraviolet Rays ,Photoaging ,Pharmacology ,Toxicology ,medicine.disease_cause ,Antioxidants ,Article ,Cell Line ,chemistry.chemical_compound ,Mice ,medicine ,Animals ,Sunburn ,skin and connective tissue diseases ,Skin ,biology ,integumentary system ,NF-kappa B ,medicine.disease ,Quercitrin ,Oxidative Stress ,chemistry ,Biochemistry ,Epidermal Cells ,Gene Expression Regulation ,Catalase ,biology.protein ,Quercetin ,Skin cancer ,Reactive Oxygen Species ,Oxidative stress ,DNA Damage - Abstract
Exposure of the skin to ultraviolet B (UVB) radiation causes oxidative damage to skin, resulting in sunburn, photoaging, and skin cancer. It is generally believed that the skin damage induced by UV irradiation is a consequence of generation of reactive oxygen species (ROS). Recently, there is an increased interest in the use of natural products as chemopreventive agents for non-melanoma skin cancer (NMSC) due to their antioxidants and anti-inflammatory properties. Quercitrin, glycosylated form of quercetin, is the most common flavonoid in nature with antioxidant properties. The present study investigated the possible beneficial effects of quercitrin to inhibit UVB irradiation-induced oxidative damage in vitro and in vivo. Our results showed that quercitrin decreased ROS generation induced by UVB irradiation in JB6 cells. Quercitrin restored catalase expression and GSH/GSSG ratio reduced by UVB exposure, two major antioxidant enzymes, leading to reductions of oxidative DNA damage and apoptosis and protection of the skin from inflammation caused by UVB exposure. The present study demonstrated that quercitrin functions as an antioxidant against UVB irradiation-induced oxidative damage to skin.
- Published
- 2013
32. Apigenin suppresses migration and invasion of transformed cells through down-regulation of C-X-C chemokine receptor 4 expression
- Author
-
Jia Luo, Gang Chen, Young-Ok Son, Lei Wang, Amit Budhraja, Zhuo Zhang, Xin Wang, Jeong-Chae Lee, John Andrew Hitron, Xianglin Shi, Poyil Pratheeshkumar, and Lisha Kuang
- Subjects
Chemokine ,Receptors, CXCR4 ,Cell Survival ,Blotting, Western ,Down-Regulation ,Toxicology ,medicine.disease_cause ,Transfection ,CXCR4 ,Article ,Chemokine receptor ,chemistry.chemical_compound ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Immunoprecipitation ,Neoplasm Invasiveness ,Apigenin ,Luciferases ,Pharmacology ,Wound Healing ,biology ,NF-kappa B ,Environmental exposure ,Molecular biology ,Xenograft Model Antitumor Assays ,Cell Transformation, Neoplastic ,chemistry ,Microscopy, Fluorescence ,Cancer cell ,Cancer research ,biology.protein ,Carcinogenesis ,Plasmids - Abstract
Environmental exposure to arsenic is known to cause various cancers. There are some potential relationships between cell malignant transformation and C-X-C chemokine receptor type 4 (CXCR4) expressions. Metastasis, one of the major characteristics of malignantly transformed cells, contributes to the high mortality of cells. CXCR4 and its natural chemokine ligand C-X-C motif ligand 12 (CXCL12) play a critical role in metastasis. Therefore, identification of nutritional factors which are able to inhibit CXCR4 is important for protection from environmental arsenic-induced carcinogenesis and for abolishing metastasis of malignantly transformed cells. The present study demonstrates that apigenin (4′, 5, 7-trihydroxyflavone), a natural dietary flavonoid, suppressed CXCR4 expression in arsenic-transformed Beas-2B cells (B-AsT) and several other type of transformed/cancer cells in a dose- and time-dependent manner. Neither proteasome nor lysosome inhibitor had any effect in reducing the apigenin-induced down-regulation of CXCR4, indicating that apigenin-induced down-regulation of CXCR4 is not due to proteolytic degradation. The down-regulation of CXCR4 is mainly due to the inhibition of nuclear factor κB (NF-κB) transcriptional activity. Apigenin also abolished migration and invasion of transformed cells induced by CXCL12. In a xenograft mouse model, apigenin down-regulated CXCR4 expression and suppressed tumor growth. Taken together, our results show that apigenin is a novel inhibitor of CXCR4 expression. This dietary flavonoid has the potential to suppress migration and invasion of transformed cells and prevent environmental arsenic-induced carcinogenesis.
- Published
- 2013
33. Chromium(VI), Oxidative Cell Damage
- Author
-
Young-Ok Son, John Andrew Hitron, and Xianglin Shi
- Published
- 2013
34. Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways
- Author
-
Young-Ok Son, Amit Budhraja, Xianglin Shi, Lei Wang, Jeong-Chae Lee, Mei Xu, Songze Ding, Poyil Pratheeshkumar, Xin Wang, Andrew Hitron, Jia Luo, Gang Chen, and Zhuo Zhang
- Subjects
Male ,Phytochemistry ,Angiogenesis ,Phytopharmacology ,Tumor Physiology ,Cancer Treatment ,Angiogenesis Inhibitors ,Apoptosis ,Chick Embryo ,Biochemistry ,Neovascularization ,Mice ,0302 clinical medicine ,Drug Discovery ,Basic Cancer Research ,heterocyclic compounds ,Phosphorylation ,Aorta ,Tube formation ,0303 health sciences ,Multidisciplinary ,Neovascularization, Pathologic ,TOR Serine-Threonine Kinases ,Prostate Cancer ,Prostate ,Prostate Diseases ,Ribosomal Protein S6 Kinases, 70-kDa ,Animal Models ,3. Good health ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Chemistry ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Quercetin ,Antiangiogenesis Therapy ,medicine.symptom ,Signal Transduction ,Research Article ,medicine.medical_specialty ,Science ,Urology ,Biology ,03 medical and health sciences ,Model Organisms ,Internal medicine ,Cell Line, Tumor ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Viability assay ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Nutrition ,Prostatic Neoplasms ,Cancers and Neoplasms ,Kinase insert domain receptor ,Vascular Endothelial Growth Factor Receptor-2 ,Xenograft Model Antitumor Assays ,Rats ,Genitourinary Tract Tumors ,Endocrinology ,Cancer research ,Proto-Oncogene Proteins c-akt ,Ex vivo - Abstract
Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.
- Published
- 2012
35. Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling
- Author
-
Young-Ok Son, Pratheeshkumar Poyil, Zhuo Zhang, Jeong-Chae Lee, Xianglin Shi, J. Andrew Hitron, Amit Budhraja, and Lei Wang
- Subjects
inorganic chemicals ,Blotting, Western ,SOD2 ,Mice, Nude ,Bronchi ,Respiratory Mucosa ,Toxicology ,medicine.disease_cause ,Transfection ,Article ,Cell Line ,Superoxide dismutase ,Glycogen Synthase Kinase 3 ,Mice ,Phosphatidylinositol 3-Kinases ,Cell Movement ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Protein kinase B ,PI3K/AKT/mTOR pathway ,beta Catenin ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Glycogen Synthase Kinase 3 beta ,biology ,Molecular biology ,Xenograft Model Antitumor Assays ,Oncogene Protein v-akt ,Cell Transformation, Neoplastic ,chemistry ,biology.protein ,Cancer research ,Carcinogens ,Signal transduction ,Carcinogenesis ,Reactive Oxygen Species ,Cadmium ,Plasmids ,Signal Transduction - Abstract
Cadmium has been widely used in industry and is known to be carcinogenic to humans. Although it is widely accepted that chronic exposure to cadmium increases the incidence of cancer, the mechanisms underlying cadmium-induced carcinogenesis are unclear. The main aim of this study was to investigate the role of reactive oxygen species (ROS) in cadmium-induced carcinogenesis and the signal transduction pathways involved. Chronic exposure of human bronchial epithelial BEAS-2B cells to cadmium induced cell transformation, as evidenced by anchorage-independent growth in soft agar and clonogenic assays. Chronic cadmium treatment also increased the potential of these cells to invade and migrate. Injection of cadmium-stimulated cells into nude mice resulted in the formation of tumors. In contrast, the cadmium-mediated increases in colony formation, cell invasion and migration were prevented by transfection with catalase, superoxide dismutase-1 (SOD1), or SOD2. In particular, chronic cadmium exposure led to activation of signaling cascades involving PI3K, AKT, GSK-3β, and β-catenin and transfection with each of the above antioxidant enzymes markedly inhibited cadmium-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the cadmium-mediated increase in total and active β-catenin proteins and colony formation. Moreover, there was a marked induction of AKT, GSK-3β, β-catenin, and carcinogenic markers in tumor tissues formed in mice after injection with cadmium-stimulated cells. Collectively, our findings suggest a direct involvement of ROS in cadmium-induced carcinogenesis and implicate a role of AKT/GSK-3β/β-catenin signaling in this process.
- Published
- 2012
36. Cadmium induces autophagy through ROS-dependent activation of the LKB1-AMPK signaling in skin epidermal cells
- Author
-
Young-Ok Son, Senping Cheng, Xin Wang, Songze Ding, Amit Budhraja, Xianglin Shi, Jeong-Chae Lee, Zhuo Zhang, and John Andrew Hitron
- Subjects
inorganic chemicals ,Small interfering RNA ,AMP-Activated Protein Kinases ,Protein Serine-Threonine Kinases ,Toxicology ,Article ,Cell Line ,Superoxide dismutase ,Mice ,Autophagy ,Animals ,PI3K/AKT/mTOR pathway ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,AMPK ,Transfection ,Cell biology ,chemistry ,Cell culture ,biology.protein ,Epidermis ,Reactive Oxygen Species ,Cadmium ,Signal Transduction - Abstract
Cadmium is a toxic heavy metal which is environmentally and occupationally relevant. The mechanisms underlying cadmium-induced autophagy are not yet completely understood. The present study shows that cadmium induces autophagy, as demonstrated by the increase of LC3-II formation and the GFP-LC3 puncta cells. The induction of autophagosomes was directly visualized by electron microscopy in cadmium-exposed skin epidermal cells. Blockage of LKB1 or AMPK by siRNA transfection suppressed cadmium-induced autophagy. Cadmium-induced autophagy was inhibited in dominant-negative AMPK-transfected cells, whereas it was accelerated in cells transfected with the constitutively active form of AMPK. mTOR signaling, a negative regulator of autophagy, was downregulated in cadmium-exposed cells. In addition, cadmium generated reactive oxygen species (ROS) at relatively low levels, and caused poly(ADP-ribose) polymerase-1 (PARP) activation and ATP depletion. Inhibition of PARP by pharmacological inhibitors or its siRNA transfection suppressed ATP reduction and autophagy in cadmium-exposed cells. Furthermore, cadmium-induced autophagy signaling was attenuated by either exogenous addition of catalase and superoxide dismutase, or by overexpression of these enzymes. Consequently, these results suggest that cadmium-mediated ROS generation causes PARP activation and energy depletion, and eventually induces autophagy through the activation of LKB1-AMPK signaling and the down-regulation of mTOR in skin epidermal cells.
- Published
- 2011
37. NADPH Oxidase Activation Is Required in Reactive Oxygen Species Generation and Cell Transformation Induced by Hexavalent Chromium
- Author
-
Xin Wang, Xianglin Shi, Young-Ok Son, Qingshan Chang, Amit Budhraja, Fei Chen, Lijuan Sun, J. Andrew Hitron, Zun-Ji Ke, Zhuo Zhang, and Jia Luo
- Subjects
inorganic chemicals ,Chromium ,Antioxidant ,Cell Survival ,medicine.medical_treatment ,Mice, Nude ,Bronchi ,Toxicology ,medicine.disease_cause ,Transfection ,Cell Line ,Mice ,Neoplasms ,medicine ,Chromates ,Animals ,Humans ,Gene Silencing ,Phosphorylation ,RNA, Small Interfering ,chemistry.chemical_classification ,Reactive oxygen species ,NADPH oxidase ,Carcinogenicity ,biology ,Cell growth ,Glutathione peroxidase ,Cell Membrane ,NADPH Oxidases ,Epithelial Cells ,Molecular biology ,Xenograft Model Antitumor Assays ,Enzyme Activation ,Oxidative Stress ,Cell Transformation, Neoplastic ,chemistry ,Catalase ,cardiovascular system ,biology.protein ,Carcinogens ,Dismutase ,Oxidoreductases ,Reactive Oxygen Species ,Oxidative stress ,Neoplasm Transplantation - Abstract
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Although overproduction of reactive oxygen species (ROS) has been suggested to play a major role in its carcinogenicity, the mechanisms of Cr(VI)-induced ROS production remain unclear. In this study, we investigated the role of NADPH oxidase (NOX), one of the major sources of cellular ROS, in Cr(VI)-induced oxidative stress and carcinogenesis. We found that short-term exposure to Cr(VI) (2μM) resulted in a rapid increase in ROS generation in Beas-2B cells, and concomitantly increased NOX activity and expression of NOX members (NOX1-3 and NOX5) and subunits (p22(phox), p47(phox), p40(phox), and p67(phox)). Cr(VI) also induced phosphorylation of p47(phox) and membrane translocation of p47(phox) and p67(phox), further confirming NOX activation. Knockdown of p47(phox) with a short hairpin RNA attenuated the ROS production induced by Cr(VI). Chronic exposure (up to 3 months) to low doses of Cr(VI) (0.125, 0.25, and 0.5μM) also promoted ROS generation and the expression of NOX subunits, such as p47(phox) and p67(phox), but inhibited the expression of main antioxidant enzymes, such as superoxidase dismutase (SOD) and glutathione peroxidase (GPx). Chronic Cr(VI) exposure resulted in transformation of Beas-2B cells, increasing cell proliferation, anchorage independent growth in soft agar, and forming aggressive tumors in nude mice. Stable knockdown of p47(phox) or overexpression of SOD1, SOD2, or catalase (CAT) eliminated Cr(VI)-induced malignant transformation. Our results suggest that NOX plays an important role in Cr(VI)-induced ROS generation and carcinogenesis.
- Published
- 2011
38. The Dual Roles of c-Jun NH2-Terminal Kinase Signaling in Cr(VI)-Induced Apoptosis in JB6 Cells
- Author
-
Amit Budhraja, Zhuo Zhang, Young-Ok Son, Senping Cheng, John Andrew Hitron, Nancy Lan Guo, Jeong-Chae Lee, and Xianglin Shi
- Subjects
Chromium ,Expression of Concern ,Programmed cell death ,Blotting, Western ,Apoptosis ,Toxicology ,Cell Line ,Mice ,Downregulation and upregulation ,Superoxides ,Molecular Toxicology ,Animals ,Caspase ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Cell growth ,Electron Spin Resonance Spectroscopy ,JNK Mitogen-Activated Protein Kinases ,Molecular biology ,Cell biology ,Antiapoptotic Agent ,chemistry ,biology.protein ,Signal transduction ,Reactive Oxygen Species ,Signal Transduction - Abstract
Occupational exposure to chromium (Cr) compounds has been shown to cause serious toxic and carcinogenic effects. The skin is an important target for the compounds in industrially exposed Cr workers. c-Jun NH(2)-terminal kinase (JNK) regulates cell proliferation, apoptosis, and differentiation. This protein's effects on cellular response depend upon the cell type and stimuli. The mechanisms by which hexavalent chromium (Cr(VI)) leads to apoptosis in the skin are unclear at present. The aim of this study is to examine whether JNK regulates apoptosis in Cr(VI)-exposed mouse JB6 epidermal cells. The present study showed that Cr(VI) induced apoptotic cell death through JNK activation. The blockage of JNK by small interference RNA (si-RNA) transfection suppressed Cr(VI)-induced apoptotic cell death with the concomitant downregulation of antiapoptotic Bcl-2 family proteins, mitochondrial membrane depolarization (Δψm), caspase activation, and poly (ADP-ribose) polymerase cleavage. However, inhibition of c-Jun expression by si-RNA transfection enhanced cytotoxicity, which corresponded to increasing apoptosis and Δψm. This phenomenon is associated with p53 activation caused by increasing reactive oxygen species (ROS) levels because of the downregulation of superoxide dismutase expression in si-c-Jun-transfected cells. Taken together, Cr(VI) induces apoptosis via JNK-mediated signaling, whereas c-Jun activation acts as an inhibitor of apoptotic signaling. Additionally, ROS generated by Cr(VI) is a pivotal regulator of JNK.
- Published
- 2010
39. Cr(VI) induces mitochondrial-mediated and caspase-dependent apoptosis through reactive oxygen species-mediated p53 activation in JB6 Cl41 cells
- Author
-
Xianglin Shi, Zhuo Zhang, Xin Wang, Jingju Pan, Qingshan Chang, Young-Ok Son, J. Andrew Hitron, Jeong-Chae Lee, Shuxia Wang, and Jiankang Liu
- Subjects
Chromium ,Programmed cell death ,Cell Survival ,Poly ADP ribose polymerase ,Apoptosis ,Mitochondrion ,Toxicology ,Caspase-Dependent Apoptosis ,Article ,Cell Line ,chemistry.chemical_compound ,Mice ,Animals ,Caspase ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Dose-Response Relationship, Drug ,Chemistry ,Superoxide ,Molecular biology ,Carcinogens, Environmental ,Mitochondria ,Biochemistry ,Caspases ,biology.protein ,Tumor Suppressor Protein p53 ,Reactive Oxygen Species - Abstract
Cr(VI) compounds are known to cause serious toxic and carcinogenic effects. Cr(VI) exposure can lead to a severe damage to the skin, but the mechanisms involved in the Cr(VI)-mediated toxicity in the skin are unclear. The present study examined whether Cr(VI) induces cell death by apoptosis or necrosis using mouse skin epidermal cell line, JB6 Cl41 cells. We also investigated the cellular mechanisms of Cr(VI)-induced cell death. This study showed that Cr(VI) induced apoptotic cell death in a dose-dependent manner, as demonstrated by the appearance of cell shrinkage, the migration of cells into the sub-G1 phase, the increase of Annexin V positively stained cells, and the formation of nuclear DNA ladders. Cr(VI) treatment resulted in the increases of mitochondrial membrane depolarization and caspases activation. Electron spin resonance (ESR) and fluorescence analysis revealed that Cr(VI) increased intracellular levels of reactive oxygen species (ROS) such as hydrogen peroxide and superoxide anion radical in dose-dependent manner. Blockage of p53 by si-RNA transfection suppressed mitochondrial changes of Bcl-2 family composition, mitochondrial membrane depolarization, caspase activation and PARP cleavage, leading to the inhibition of Cr(VI)-induced apoptosis. Further, catalase treatment prevented p53 phosphorylation stimulated by Cr(VI) with the concomitant inhibition of caspase activation. These results suggest that Cr(VI) induced a mitochondrial-mediated and caspase-dependent apoptosis in skin epidermal cells through activation of p53, which are mainly mediated by reactive oxidants generated by the chemical.
- Published
- 2010
40. Moromycins A and B, isolation and structure elucidation of C-glycosylangucycline-type antibiotics from Streptomyces sp. KY002
- Author
-
Irfan Baig, Jürgen Rohr, Mohamed S. Abdelfattah, John Andrew Hitron, and Madan K. Kharel
- Subjects
Stereochemistry ,Pharmaceutical Science ,Kentucky ,Anthraquinones ,Microbial Sensitivity Tests ,Streptomyces ,Article ,Analytical Chemistry ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Cytotoxicity ,Nuclear Magnetic Resonance, Biomolecular ,Pharmacology ,Saquayamycin ,Antibiotics, Antineoplastic ,biology ,Molecular Structure ,Streptomycetaceae ,Organic Chemistry ,biology.organism_classification ,Complementary and alternative medicine ,chemistry ,Biochemistry ,Cell culture ,Molecular Medicine ,Female ,Actinomycetales ,Drug Screening Assays, Antitumor ,Bacteria - Abstract
Two new anticancer antibiotics of the angucycline class, moromycins A and B (1, 2), along with the known microbial metabolites saquayamycin B (3) and fridamycin D (4) were isolated from the ethyl acetate extract of a culture broth of the terrestrial Streptomyces sp. KY002. The structures consist of a tetrangomycin core, and various C- and O-glycosidically linked deoxysugars. The chemical structures of the new secondary metabolites were elucidated by 1D and 2D NMR and by mass spectrometry. Moromycin B (2) showed significant cytotoxicity against H-460 human lung cancer and MCF-7 human breast cancer cells.
- Published
- 2008
41. Abstract 5360: Ethanol enhances arsenic-induced mutagenesis in colon
- Author
-
Young-Ok Son, Lisha Kuang, Zhuo Zhang, Zhigang Wang, Xianglin Shi, John Andrew Hitron, Lei Wang, Pratheeshkumar Poyil, and Jia Luo
- Subjects
Cancer Research ,education.field_of_study ,Oxidase test ,DNA damage ,business.industry ,Population ,Mutagenesis ,chemistry.chemical_element ,Environmental exposure ,medicine.disease_cause ,Toxicology ,Oncology ,chemistry ,In vivo ,Cancer research ,medicine ,education ,Carcinogenesis ,business ,Arsenic - Abstract
Health effects due to environmental exposure to arsenic are a major health concern world-wide. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. As one of the common nutritional factors, ethanol is also a well-documented risk factor for many malignancies. However, little is known on the effects of co-exposure to arsenic and ethanol in mutagenesis and carcinogenesis. In this study, we investigate the mutagenic effect of co-exposure to arsenic and ethanol in vivo and in vitro. Results show that ethanol could markedly enhance arsenic-induced mutagenesis in colon in Big Blue Mice. This response related to intracellular reactive oxygen species (ROS) generation, NAPDH oxidase activation, and DNA damage/repair functional changes. We conclude that ethanol enhances arsenic-induced mutagenesis in colon in vivo. These results indicated that alcohol consumption should be taken into consideration in the investigation on arsenic-induced carcinogenesis in arsenic-exposure population. Citation Format: Lei Wang, Lisha Kuang, Young-Ok Son, John Andrew Hitron, Pratheeshkumar Poyil, Zhuo Zhang, Jia Luo, Zhigang Wang, Xianglin Shi. Ethanol enhances arsenic-induced mutagenesis in colon. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5360. doi:10.1158/1538-7445.AM2014-5360
- Published
- 2014
42. Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis
- Author
-
Jia Luo, Amit Budhraja, Gang Chen, Zhuo Zhang, Songze Ding, Andrew Hitron, Xin Wang, Donghern Kim, Jeong-Chae Lee, Young-Ok Son, Lei Wang, Xianglin Shi, Poyil Pratheeshkumar, and Sasidharan Padmaja Divya
- Subjects
Male ,CD31 ,Phytochemistry ,Angiogenesis ,Phytopharmacology ,Phytochemicals ,Cancer Treatment ,Chick Embryo ,Toxicology ,Biochemistry ,Chorioallantoic Membrane ,Neovascularization ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Drug Discovery ,Extracellular Signal-Regulated MAP Kinases ,Luteolin ,Aorta ,0303 health sciences ,Multidisciplinary ,Neovascularization, Pathologic ,TOR Serine-Threonine Kinases ,Prostate Cancer ,Prostate Diseases ,Ribosomal Protein S6 Kinases, 70-kDa ,Animal Models ,Chemistry ,Oncology ,030220 oncology & carcinogenesis ,Cytokines ,Medicine ,Antiangiogenesis Therapy ,medicine.symptom ,Cancer Prevention ,Signal Transduction ,Research Article ,Biotechnology ,medicine.medical_specialty ,Cell Survival ,Science ,Urology ,In Vitro Techniques ,Biology ,03 medical and health sciences ,Model Organisms ,Cell Line, Tumor ,Internal medicine ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Nutrition ,030304 developmental biology ,Prostatic Neoplasms ,Cancers and Neoplasms ,Kinase insert domain receptor ,Chemotherapy and Drug Treatment ,Vascular Endothelial Growth Factor Receptor-2 ,Xenograft Model Antitumor Assays ,Matrix Metalloproteinases ,Rats ,Endocrinology ,chemistry ,Microvessels ,Cancer research ,Proto-Oncogene Proteins c-akt ,Ex vivo - Abstract
Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
- Published
- 2012
43. Abstract 4593: Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in athymic nude mice
- Author
-
Pooja Gupta, Ning Gao, Young-Ok Son, Zhou Zhang, Andrew Hitron, Xianglin Shi, Amit Budhraja, and Songze Ding
- Subjects
Cancer Research ,biology ,HL60 ,business.industry ,medicine.disease ,Jurkat cells ,Leukemia ,chemistry.chemical_compound ,Oncology ,chemistry ,Apoptosis ,Immunology ,Apigenin ,medicine ,biology.protein ,Cancer research ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Caspase - Abstract
Purpose of the study: To investigate the functional role of Akt and JNK signaling cascades in apigenin-induced apoptosis in human leukemia cells (in vitro) and anti-leukemic activity of apigenin in U937 xenografts (in vivo). Experimental Design: Leukemia cells were treated with apigenin in dose and time dependent manners, after which apoptosis, caspases activation, Akt and JNK signaling pathways were evaluated by pharmacologic and genetic approaches. Parallel studies were also conducted in Jurkat, HL60 and normal peripheral blood mononuclear cells. In vivo anti-leukemic activity mediated by apigenin was evaluated using U937 xenograft mouse model. Results: Exposure of apigenin caused pronounced increase in apoptosis in leukemia cells but not in normal peripheral blood mononuclear cells. Apigenin-induced apoptosis by inactivation of Akt with concomitant activation of JNK, cytochrome c release from mitochondria and caspases activation in dose and time dependent manners. Enforced activation of Akt by a constitutively active myristolated Akt prevented apigenin-induced JNK and caspases activation and apoptosis. Conversely, PI3K (phosphatidyl 3-kinase) inhibitor LY294002 and a dominant negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. In addition, Akt kinase activity was diminished after exposure to apigenin in leukemia cells. Interruption of JNK pathway by pharmacologic (SP600125) and genetic (JNK1 siRNA) approaches showed marked reduction in apigenin-induced caspases activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin via intraperitoneal route resulted in attenuation of tumor growth in U937 xenografts accompanied by apoptosis. Conclusions: Collectively, these findings suggested a hierarchical model of apigenin-induced apoptosis in human leukemia cells in which apigenin-induced Akt inactivation represents a primary event resulting in JNK activation and culminating in caspases activation and apoptosis. In addition, attenuation of tumor growth in U937 xenografts by apigenin raise the possibility that apigenin may have clinical implications for therapeutic intervention against leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4593. doi:10.1158/1538-7445.AM2011-4593
- Published
- 2011
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.