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Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CRC. It is found that RFNG depletion significantly sensitizes cancer cells to oxaliplatin treatment. Mechanistically, chemotherapy‐activated MAPK signaling induces ERK to phosphorylate RFNG Ser255 residue. Phosphorylated RFNG S255 (pS255) interacts with the nuclear importin proteins KPNA1/importin‐α1 and KPNB1/importin‐β1, leading to its translocation into the nucleus where it targets p53 and inhibits its phosphorylation by competitively inhibiting the binding of CHK2 to p53. Consequently, the expression of CDKN1A is decreased and that of SLC7A11 is increased, leading to the inhibition of apoptosis and ferroptosis. In contrast, phosphor‐deficient RFNG S225A mutant showed increased apoptosis and ferroptosis, and exhibited a notable response to oxaliplatin chemotherapy both in vitro and in vivo. It is further revealed that patients with low RFNG pS255 exhibited significant sensitivity to oxaliplatin in a patient‐derived xenograft (PDX) model. These findings highlight the crosstalk between the MAPK and p53 signaling pathways through RFNG, which mediates oxaliplatin resistance in CRC. Additionally, this study provides guidance for oxaliplatin treatment of CRC patients. [ABSTRACT FROM AUTHOR]

Background: To investigate the effects of arsenic trioxide (ATO) on human colorectal cancer cells (HCT116) growth and the role of transient receptor potential melastatin 4 (TRPM4) channel in this process. Methods: The viability of HCT116 cells was assessed using the CCK-8 assay. Western blot analysis was employed to examine the protein expression of TRPM4. The apoptosis of HCT116 cells was determined using TUNEL and Flow cytometry. Cell migration was assessed through the cell scratch recovery assay and Transwell cell migration assay. Additionally, Transwell cell invasion assay was performed to determine the invasion ability of HCT116 cells. Results: ATO suppressed the viability of HCT116 cells in a dose-dependent manner, accompanied by a decline in cell migration and invasion, and an increase in apoptosis. 9-phenanthroline (9-Ph), a specific inhibitor of TRPM4, abrogated the ATO-induced upregulation of TRPM4 expression. Additionally, blocking TRPM4 reversed the effects of ATO on HCT116 cells proliferation, including restoration of cell viability, migration and invasion, as well as the inhibition of apoptosis. Conclusion: ATO inhibits CRC cell growth by inducing TRPM4 expression, our findings indicate that ATO is a promising therapeutic strategy and TRPM4 may be a novel target for the treatment of CRC. [ABSTRACT FROM AUTHOR]

Background: Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models. Results: We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells. Conclusions: NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors. [ABSTRACT FROM AUTHOR]

This research investigated the anticancer properties of punicalagin, a prominent bioactive polyphenol extracted from Punica granatum L, in human gastric cancer cell lines. Normal and gastric cancer cells were exposed to different doses of punicalagin for various durations. Punicalagin exhibited cytotoxic effects on gastric cancer cells in a dose- and time-dependent fashion, while sparing normal gastric epithelial cells. It is noteworthy that among the 3 gastric cancer cells, HGC-27 cells were more resistant to punicalagin than 23,132/87 and AGS cells. Furthermore, punicalagin triggered apoptosis in gastric cancer cells, evidenced by a rise in both early and late apoptotic cell percentages. Western blot analysis further revealed that punicalagin elevated the levels of activated caspase-3. Conversely, punicalagin curtailed cell invasion and reduced the expression of MMP-2, MMP-9, Snail, and Slug. From a mechanistic standpoint, Western blotting indicated that punicalagin might inhibit the Erk and NF-κB pathways, leading to apoptosis induction and the inhibition of cell invasion in gastric cancer cells. These results indicate that punicalagin promotes apoptosis and inhibits cell invasion in gastric cancer cells by activating caspase-3 and suppressing MMP-2, MMP-9, Snail, and Slug through the inhibition of the Erk and NF-κB pathways. [ABSTRACT FROM AUTHOR]

Lymphomas are a heterogeneous group of diseases that originate from T, B or natural killer cells. Lymphoma treatment is based on chemotherapy, radiotherapy, and monoclonal antibody (mAb) or other immunotherapies. The P‐selectin glycoprotein ligand 1 (PSGL‐1) is expressed at the surface of hematological malignant cells and has been shown to have a pro‐oncogenic role in multiple myeloma and lymphoma. Here, we investigated the expression and therapeutic potential of PSGL‐1 in T and B cell lymphomas. By flow cytometry analysis, we found that PSGL‐1 was expressed in both T and B cell‐derived lymphoma cell lines but generally at higher levels in T cell lymphoma cell lines. For most T and B cell‐derived lymphoma cell lines, in vitro targeting with the PL1 mAb, which recognizes the PSGL‐1 N‐terminal extracellular region and blocks functional interactions with selectins, resulted in reduced cell viability. The PL1 mAb pro‐apoptotic activity was shown to be dose‐dependent, to be linked to increased ERK kinase phosphorylation, and to be dependent on the MAP kinase signaling pathway. Importantly, anti‐PSGL‐1 treatment of mice xenografted with the HUT‐78 cutaneous T‐cell lymphoma cell line resulted in decreased tumor growth, had no effect on in vivo proliferation, but increased the levels of apoptosis in tumors. Anti‐PSGL‐1 treatment of mice xenografted with a Burkitt lymphoma cell line that was resistant to anti‐PSGL‐1 treatment in vitro, had no impact on tumorigenesis. These findings show that PSGL‐1 antibody targeting triggers lymphoma cell apoptosis and substantiates PSGL‐1 as a potential target for lymphoma therapy. [ABSTRACT FROM AUTHOR]

Biological importance in many fields, including anti-cancer activity, and advances in inorganic chemistry with biological applications have heightened the scope of interest in Schiff bases and their complexes due to the combination of an aldehyde with an amine are useful chelate to produce coordination spheres with mixed N/O donors. The discovery of Schiff base and its complexes' antitumor activity against various tumor cell lines captures the interest of researchers seeking to develop new anti-cancer drugs with no side effects. O-vanillin is a very useful aldehyde for preparing Schiff base ligands. It is found in the extract of vanilla. It is readily soluble in water. This aldehyde can combine with several different types of amine to form Schiff base which can form complexes with high stability with the majority of metals, which is caused by the azomethine group's nitrogen (N) in addition to two oxygen (O) atoms from the hydroxyl and methoxy groups. Apoptosis is a natural death process of damaged, senescent, or abnormal cells that stops cancer development. It is reduced or blocked in cancer cells and can be triggered again by anti-cancer drugs. Therefore, in anti-cancer research, inducing cancer cell apoptosis is a favourable goal to be achieved by a new molecule blocked in cancer cells and can be triggered again by anti-cancer drugs. This review focuses on recent advances in N,S,O donor Schiff base molecules for Anticancer applications. [ABSTRACT FROM AUTHOR]

Antimitotic compounds, targeting key spindle assembly checkpoint (SAC) components (e.g., MPS1, Aurora kinase B, PLK1, KLP1, CENPE), are potential alternatives to microtubule-targeting antimitotic agents (e.g., paclitaxel) to circumvent resistance and side effects associated with their use. They can be classified into mitotic blockers, causing SAC-induced mitotic arrest, or mitotic drivers, pushing cells through aberrant mitosis by overriding SAC. These drugs, although advancing to clinical trials, exhibit unsatisfactory cancer treatment outcomes as monotherapy, probably due to variable cell fate responses driven by cyclin B degradation and apoptosis signal accumulation networks. We investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic navitoclax in lung cancer cells treated with the selective CENPE inhibitor GSK923295 (mitotic blocker) or the MPS1 inhibitor BAY1217389 (mitotic driver). Our aim was to steer treated cancer cells towards cell death. BH3-mimetics, in combination with both mitotic blockers and drivers, induced substantial cell death, mainly through apoptosis, in 2D and 3D cultures. Crucially, these synergistic concentrations were less toxic to non-tumor cells. This highlights the significance of combining BH3-mimetics with antimitotics, either blockers or drivers, which have reached the clinical trial phase, to enhance their effectiveness. [ABSTRACT FROM AUTHOR]

Increased neddylation benefits the survival of several types of cancer cells. The inhibition of neddylation has the potential to exert anticancer effects but is rarely assessed in oral cancer cells. This study aimed to investigate the antiproliferation potential of a neddylation inhibitor MLN4924 (pevonedistat) for oral cancer cells. MLN4924 inhibited the cell viability of oral cancer cells more than that of normal oral cells (HGF‐1) with 100% viability, that is, IC50 values of oral cancer cells (CAL 27, OC‐2, and Ca9‐22) are 1.8, 1.4, and 1.9 μM. MLN4924 caused apoptotic changes such as the subG1 accumulation, activation of annexin V, pancaspase, and caspases 3/8/9 of oral cancer cells at a greater rate than in normal oral cells. MLN4924 induced greater oxidative stress in oral cancer cells compared to normal cells by upregulating reactive oxygen species and mitochondrial superoxide and depleting the mitochondrial membrane potential and glutathione. In oral cancer cells, preferential inductions also occurred for DNA damage (γH2AX and 8‐oxo‐2′‐deoxyguanosine). Therefore, this investigation demonstrates that MLN4924 is a potential anti‐oral‐cancer agent showing preferential inhibition of apoptosis and promotion of DNA damage with fewer cytotoxic effects on normal cells. [ABSTRACT FROM AUTHOR]

Hungatella hathewayi (H. hathewayi), also known as Clostridium hathewayi, has been reported to be accumulated in the colorectal cancer (CRC) samples. In addition, evidence has demonstrated that inoculation with H. hathewayi promotes the proliferation of colonic epithelial cells in mice. Herein, we explored H. hathewayi role in regulating the 5-fluorouracil (5-FU) resistance in CRC cells, and investigated the underlying mechanisms. H. hathewayi abundance in CRC tissues and the corresponding adjacent normal tissues was tested using qRT-PCR. Both parental and 5-FU resistance CRC cell lines were used to assess H. hathewayi role in regulating the 5-FU resistance of CRC cells using CCK-8, flow cytometry and animal experiments. H. hathewayi abundance was significantly increased in CRC tissues, and the high level of H. hathewayi was linked to lower overall survival rate. H. hathewayi treatment significantly weakened 5-FU effects on inhibiting cell growth and inducing cell apoptosis in CRC HCT116 and HT29 cells. In addition, H. hathewayi enhanced the 5-FU resistance of HCT116/5-FU and HT29/5-FU cells (the 5-FU resistance cell lines). In mechanism, H. hathewayi decreased the expression of CDX2, and increased the expression of nuclear accumulation of β-catenin. Overexpression of CDX2 abolished H. hathewayi-mediated enhancement in cell growth and inhibition in cell apoptosis in HCT116/5-FU and HT29/5-FU cells, as well as inhibited the expression and nuclear accumulation of β-catenin. In conclusion, H. hathewayi abundance was increased in CRC tissues, and the high level of H. hathewayi was linked to lower overall survival rate. In mechanisam, H. hathewayi treatment enhanced the 5-FU resistance of CRC cells through modulating CDX2/β-catenin signaling. [ABSTRACT FROM AUTHOR]

Hsp27 phosphorylation is associated with many pathways in glioma, such as tumor cell proliferation and apoptosis inhibition. The aim of this study is to examine the separate and mutual effects of BIRB796 and bortezomib on pHsp27 and to investigate their effects on the viability of U87MG glioma cells. At the same time, the effects of the agents on the p38MAPK enzyme and caspase 3, which plays a role in the mechanism of apoptosis, were also investigated. The cytotoxic effect of bortezomib and BIRB796 on U87MG cells was investigated by MTT method. Hsp27 and pHsp27 proteins expression levels were exhibited by Western Blot analysis. Also, we examined the effects of BIRB796 on p38MAPK (α, β) enzyme inhibition and caspase 3 activity. According to the MTT results, BIRB796 did not significantly reduce cell proliferation in a dose-dependent manner, but bortezomib significantly reduced it in a dose and time-dependent manner. In Western blot analyses, 5 nM bortezomib, and 100, 250, 500 nM BIRB796 concentrations that show neither a cytotoxic nor a proliferative effect on the cells were used as combined treatment. It was seen that 5 nM bortezomib treatment significantly induced pHsp27 (76%) and Hsp27 (48%) expression levels in the glioma cells. Also it was found that BIRB796 treatments significantly decreased the level of Hsp27 and pHsp27. The combined treatments significantly reduced pHsp27 expression level. Our results showed that all treatments also significantly increased caspase 3 activation. In addition, BIRB796 inhibited p38α and p38β activities depending on time, and this agent effect on p38α was stronger than p38β. All results indicate that BIRB796 and bortezomib have additive effects on cell viability and caspase 3. Also BIRB796 agent may be an effective therapeutic option in cancer cells by reducing cell resistance, apoptosis and pHsp27 expression in the treatment of brain cancer. [ABSTRACT FROM AUTHOR]

Scoparia dulcis Linn plays an important role in treatment because it contains active compounds that are proven to have a variety of activities, including cytotoxicity on various cancer cells. The objective of this study is to isolate and identify the cytotoxic compounds in the ethyl acetate fraction of Scoparia dulcis, observe cell cycle inhibition and induction of apoptosis in vitro, and carry out molecular studies using in silico studies. A new diterpene compound was isolated from the ethyl acetate fraction of Scoparia dulcis L. of Indonesian origin. Chromatographic methods were used to isolate the compound, spectroscopic methods were used to elucidate its structure, and these data were compared with those reported in the literature. The compound was tested for its cytotoxic activity against two breast cancer cells (MCF-7 and T47D). The results of the isolated compound showed a cytotoxic effect on MCF-7 and T47D breast cancer cells at IC50 70.56 ± 1.54 and <3.125 ± 0.43 µg/mL, respectively. The compound inhibited the growth of MCF-7 and T47D breast cancer cells and the accumulation of cells in the G1 phases, and it induced apoptosis. Based on a spectroscopic analysis, the isolated compound was identified as 2α-hydroxyscopadiol, which is a new diterpenoid. A docking study revealed that the isolate's hydroxyl groups are essential for interacting with crucial residues on the active sites of the ER and PR and caspase-9. The isolate inhibits ER and PR activity with binding energies of −8.2 kcal/mol and −7.3 kcal/mol, respectively. In addition, the isolate was also able to induce apoptosis through the activation of the caspase-9 pathway with an affinity of −9.0 kcal/mol. In conclusion, the isolated compound from S. dulcis demonstrated anticancer activity based on in vitro and in silico studies. [ABSTRACT FROM AUTHOR]

Background: It is well established that inflammation and platelets promote multiple processes of cancer malignancy. Recently, platelets have received attention for their role in carcinogenesis through the production of microvesicles or platelet-derived microparticles (PMPs), which transfer their biological content to cancer cells. We have previously characterized a new subpopulation of these microparticles (termed mito-microparticles), which package functional mitochondria. The potential of mitochondria transfer to cancer cells is particularly impactful as many aspects of mitochondrial biology (i.e., cell growth, apoptosis inhibition, and drug resistance) coincide with cancer hallmarks and disease progression. These metabolic aspects are particularly notable in chronic lymphocytic leukemia (CLL), which is characterized by a relentless accumulation of proliferating, immunologically dysfunctional, mature B-lymphocytes that fail to undergo apoptosis. The present study aimed to investigate the role of PMPs on CLL metabolic plasticity leading to cancer cell phenotypic changes. Methods: CLL cell lines were co-incubated with different concentrations of human PMPs, and their impact on cell proliferation, mitochondrial DNA copy number, OCR level, ATP production, and ROS content was evaluated. Essential genes involved in metabolic-reprogramming were identified using the bioinformatics tools, examined between patients with early and advanced CLL stages, and then validated in PMP-recipient CLLs. Finally, the impact of the induced metabolic reprogramming on CLLs' growth, survival, mobility, and invasiveness was tested against anti-cancer drugs Cytarabine, Venetoclax, and Plumbagin. Results: The data demonstrated the potency of PMPs in inducing tumoral growth and invasiveness in CLLs through mitochondrial internalization and OXPHOS stimulation which was in line with metabolic shift reported in CLL patients from early to advanced stages. This metabolic rewiring also improved CLL cells' resistance to Cytarabine, Venetoclax, and Plumbagin chemo drugs. Conclusion: Altogether, these findings depict a new platelet-mediated pathway of cancer pathogenesis. We also highlight the impact of PMPs in CLL metabolic reprogramming and disease progression. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) remains a major life-threatening malignancy, despite numerous therapeutic and screening attempts. Apoptosis and autophagy are two processes that share common signaling pathways, are linked by functional relationships and have similar protein components. During the development of cancer, the two processes can trigger simultaneously in the same cell, causing, in some cases, an inhibition of autophagy by apoptosis or apoptosis by autophagy. Malignant cells that have accumulated genetic alterations can take advantage of any alterations in the apoptotic process and as a result, progress easily in the cancerous transformation. Autophagy often plays a suppressive role during the initial stages of carcinogenicity, while in the later stages of cancer development it can play a promoting role. It is extremely important to determine the regulation of this duality of autophagy in the development of CRC and to identify the molecules involved, as well as the signals and the mechanisms behind it. All the reported experimental results indicate that, while the antagonistic effects of autophagy and apoptosis occur in an adverse environment characterized by deprivation of oxygen and nutrients, leading to the formation and development of CRC, the effects of promotion and collaboration usually involve an auxiliary role of autophagy compared to apoptosis. In this review, we elucidate the different roles of autophagy and apoptosis in human CRC development. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of circ_0016788 targeting miR-338-3p on the proliferation, apoptosis, migration and invasion of prostate cancer cells. Methods circ_0016788 and miR-338-3p expressions were detected by RT-qPCR in prostate cancer tissues.si-circ_0016788, si-NC, miR-NC, miR-338-3p mimic, si-circ_0016788+anti-miR-NC, si-circ_0016788+ anti-miR-338-3p were transfected into DU145 cells respectively. CCK-8, Transwell method and flow cytometry were applied to detect DU145 cells growth, migration, invasion and apoptosis rate. The interaction between circ_0016788 and miR-338-3p was confirmed by dual luciferase reporter assay. Results circ_0016788 was highly expressed（P＜0.05） while miR-338-3p was lowly expressed（P＜0.05） in prostate cancer tissues. After inhibiting the expression of circ_0016788, the cell inhibition rate, apoptosis rate and miR-338-3p expression level were increased（P＜0.05）, and the numbers of migration and invasion were decreased（P＜0.05）. After overexpression of circ_0016788, the cell inhibition rate and apoptosis rate were decreased（P＜0.05）, and the numbers of migration and invasion were increased（P＜0.05）. miR-338-3p was a direct target gene of circ_0016788. Inhibition of miR-338-3p expression significantly attenuated the effects of circ_0016788 low expression on DU145 cells inhibition rate, migration and invasion number, and cell apoptosis rate（P＜0.05）. Conclusion Inhibition of circ_0016788 can induce prostate cancer cell apoptosis and inhibit proliferation, migration and invasion by promoting miR-338-3pexpression. [ABSTRACT FROM AUTHOR]

Basal‐like breast cancer (BBC) and glioblastoma multiforme (GBM) are poor‐prognosis cancers that lack effective targeted therapies and harbor embryonic stem gene expression signatures. Recently, our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 (a cell‐permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block transcriptional regulation) on BBC and GBM cell viability. We treated a set of BBC and GBM cancer cell lines with increasing concentrations of AS1842856 and found reduced colony formation. Treatment of BBC and GBM cancer cells with AS1842856 led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide. Treatment with another FOXO1 inhibitor AS1708727 or FOXO1 RNAi also led to FAS induction. This work is the first to show that targeting BBC and GBM with FOXO1 inhibition leads to apoptosis. These novel findings may ultimately expand the repertoire of therapies for poor‐prognosis cancers. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors have been employed in the treatment of relapsed multiple myeloma and mantle cell lymphoma. The observed toxicity caused by proteasome inhibitors is a universal phenotype in numerous cancer cells with different sensitivity. In this study, we investigate the conserved mechanisms underlying the toxicity of the proteasome inhibitor bortezomib using gene editing approaches. Our findings utilizing different caspase knocking out cells reveal that bortezomib induces classic intrinsic apoptosis by activating caspase-9 and caspase-3/7, leading to pore-forming protein GSDME cleavage and subsequent lytic cell death or called secondary necrosis, a phenotype also observed in many apoptosis triggers like TNFα plus CHX, DTT and tunicamycin treatment in HeLa cells. Furthermore, through knocking out of nearly all BH3-only proteins including BIM, BAD, BID, BMF and PUMA, we demonstrate that NOXA is the sole BH3-only protein responsible for bortezomib-induced apoptosis. Of note, NOXA is well known for selectively binding to MCL-1 and A1, but our studies utilizing different BH3 mimetics as well as immunoprecipitation assays indicate that, except for the constitutive interaction of NOXA with MCL-1, the accumulation of NOXA after bortezomib treatment allows it to interact with BCL-XL, then simultaneous relieving suppression on apoptosis by both anti-apoptotic proteins BCL-XL and MCL-1. In addition, though bortezomib-induced significant ER stress and JNK activation were observed in the study, further genetic depletion experiments prove that bortezomib-induced apoptosis occurs independently of ER stress-related apoptosis factor CHOP and JNK. In summary, these results provide a solid conclusion about the critical role of NOXA in inactivation of BCL-XL except MCL-1 in bortezomib-induced apoptosis. • Bortezomib induces apoptosis with "blowing bubbles" phenotype mediated by GSDME. • NOXA is the sole BH3-protein responsible for bortezomib-induced apoptosis. • NOXA relieves both BCL-XL and MCL-1 suppression after bortezomib exposure. • CHOP and JNK are not required for bortezomib-induced apoptosis. [ABSTRACT FROM AUTHOR]

Isoorientin (ISO) is a flavonoid compound containing a luteolin structure, which can induce autophagy in some tumor cells. This study investigated the impact of ISO in gastric cancer AGS cells, and performed an experimental analysis on the main signaling pathways and transduction pathways it regulates. CCK–8 assay results showed that ISO reduced the survival rate of gastric cancer AGS cells, but the toxicity to normal cells was minimal. Hoechst 33342/PI double staining assay results showed that ISO induced apoptosis in gastric cancer AGS cells. Further analysis by flow cytometry and Western blot showed that ISO induced apoptosis via a mitochondria-dependent pathway. In addition, the level of reactive oxygen species (ROS) in gastric cancer AGS cells also increased with the extension of the ISO treatment time. However, cell apoptosis was inhibited by preconditioning cells with N–acetylcysteine (NAC). Moreover, ISO arrested the cell cycle at the G2/M phase by increasing intracellular ROS levels. Cell migration assay results showed that ISO inhibited cell migration by inhibiting the expression of p–AKT, p–GSK–3β, and β–catenin and was also related to the accumulation of ROS. These results suggest that ISO-induced cell apoptosis by ROS–mediated MAPK/STAT3/NF–κB signaling pathways inhibited cell migration by regulating the AKT/GSK–3β/β–catenin signaling pathway in gastric cancer AGS cells. [ABSTRACT FROM AUTHOR]

Cytochrome c (cyt c) is an electron transporter of the mitochondrial respiratory chain. Upon permeabilization of the mitochondrial outer membrane, cyt c is released into the cytoplasm, where it triggers the intrinsic pathway of apoptosis. Cytoplasmic cyt c can further reach the bloodstream. Apoptosis inhibition is one of the hallmarks of cancer and its induction in tumors is a widely used therapeutic approach. Apoptosis inhibition and induction correlate with decreased and increased serum levels of cyt c, respectively. The quantification of cyt c in the serum is useful in the monitoring of patient response to chemotherapy, with potential prognosis value. Several highly sensitive biosensors have been developed for the quantification of cyt c levels in human serum. Moreover, the delivery of exogenous cyt c to the cytoplasm of cancer cells is an effective approach for inducing their apoptosis. Similarly, several protein-based and nanoparticle-based systems have been developed for the therapeutic delivery of cyt c to cancer cells. As such, cyt c is a human protein with promising value in cancer prognosis and therapy. In addition, its thermal stability can be extended through PEGylation and ionic liquid storage. These processes could contribute to enhancing its therapeutic exploitation in clinical facilities with limited refrigeration conditions. Here, I discuss these research lines and how their timely conjunction can advance cancer therapy and prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Hypoxia has crucial functions in the development and metastasis of cervical cancer by inducing the expression of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells.Methods: We conducted RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) experiments to investigate the targets of HIF-3α or miR-630. ChIP-qPCR and RT-qPCR were carried out to validate the results of ChIP-seq and RNA-seq. Cellular, molecular, and radiation experiments were conducted to explore the functions of miR-630.Results: In this study, we showed that hypoxia-induced overexpression of HIF-3α increased the expression of dozens of miRNAs, including miR-630. Hypoxia could also directly induce miR-630 expression. ChIP-seq data showed that HIF-3α activates miR-630 expression by directly binding to the promoter of its host gene. Meanwhile, stable overexpression of miR-630 increased the expression of HIF-3α, but repressed the expression of HIF-1α, indicating a positive feedback loop between HIF-3α and miR-630. Consequently, stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Meanwhile, inhibition of miR-630 showed opposite features.Conclusion: Taken together, our findings indicate a novel hypoxia-induced HIF-3α and miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells and suggest that HIF-3α and miR-630 might act as potential biomarkers and therapeutic targets for cervical cancer in the future. [ABSTRACT FROM AUTHOR]

The presence of apoptosis inhibition proteins renders the cancer cells resistant to apoptosis, severely compromising the antitumor efficacy of sonodynamic therapy (SDT). Here, an intelligent anticancer nanoplatform based on an Aza‐boron‐dipyrromethene dye (denoted as Aza‐BDY) is elaborately established for ferroptosis augmented SDT through cysteine (Cys) starvation. After endocytosis by tumor cells, Aza‐BDY serves as both a ferroptosis inducing agent and a sonosensitizer for tumor treatment. The specific Cys response facilitates the disruption of redox homeostasis and initiation of cellular ferroptosis. Meanwhile, the released sonosensitizer causes efficient SDT and augments ferroptosis under ultrasound irradiation. Detailed in vitro and in vivo investigations demonstrate that the synergistic effect of Cys depletion and singlet oxygen (1O2) generation significantly induces cancer‐cell death and suppresses tumor proliferation with a high inhibition rate of 97.5 %. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma is one of the most common malignancies in genitourinary cancers. In China, the incidence of renal cell carcinoma has been increasing year by year. Regulated cell death is a cell-independent and orderly death controlled by genes, which is ubiquitous in organisms and plays a crucial role in maintaining the cell homeostasis. Recently, cuproptosis was reported in Science, which further reinforced the importance of cell death in living organisms. With the increasing understanding of regulated cell death, more and more studies have shown that regulated cell death (such as ferroptosis, autophagy, pyroptosis) is closely related to the tumorigenesis and development of renal cell carcinoma. For example, induction of ferroptosis inhibits the invasion and metastasis of renal cell carcinoma and is closely related with better prognosis; pyroptosis not only induce renal cancer cell death and also activate the immune-response against renal cancer; autophagy plays a "bidirectional" role in renal cell carcinoma, which can inhibit the growth of renal cell carcinoma cells but may weaken the efficacy of combinational therapy; inhibition of apoptosis and necrotizing apoptosis can significantly promote the proliferation and invasion of renal cell carcinoma. This review has summarized the molecular mechanisms of ferroptosis, pyroptosis, autophagy, apoptosis and necrotizing apoptosis and the advances of different regulatory cell death in the tumorigenesis and development of renal cell carcinoma to provide a new perspective for exploring the mechanisms of tumorigenesis and potential targets of treatment. [ABSTRACT FROM AUTHOR]

• Exosomes, after being produced from tumor cells, can also affect the functions of other cells in this microenvironment. • Exosomes from different sources, including tumor cells and immune cells, can be used in the treatment of cancers. • Exosomes have a high therapeutic potential in the treatment of tumors of various origins. • Exosomes derived from different sources contribute to tumor regression. Today, cancer treatment is one of the main challenges for researchers. The main cause of tumor cell formation is mutations that lead to uncontrolled proliferation and inhibition of apoptosis in malignant cells. Tumor cells also create a microenvironment that can suppress the immune system cells' responses through various methods, including producing soluble factors and cell-to-cell communication. After being produced from tumor cells, exosomes can also affect the functions of other cells in this microenvironment. Various studies have shown that exosomes from different sources, including tumor cells and immune cells, can be used to treat cancers due to their characteristics. Since tumor cells are rich sources of various types of tumor peptides, they can induce anti-tumor responses. Immune cells also produce exosomes that mimic the functions of their cells of origin, such that exosomes derived from NK cells and CTLs can directly lead to their apoptosis after merging with tumor cells. However, many researchers have pointed out that naïve exosomes have a limited therapeutic function, and their therapeutic potential can be increased by manipulating and engineering them. There are various methods to modify exosomes and improve their therapeutic potential. In general, these methods are divided into two parts, which include changing the cell of origin of the exosome and encapsulating the exosome to carry different drugs. In this review, we will discuss the studies on the therapeutic use of naive and engineered exosomes and provide an update on new studies in this field. [ABSTRACT FROM AUTHOR]

To investigate whether tricyclic decylbenzoxazole (TDB) regulates liver cancer cell proliferation and apoptosis through p300-mediated FOXO acetylation. Sequencing, adenovirus, and lentivirus transfection were performed in human liver cancer cell line SMMC-7721 and apoptosis was detected by Tunel, Hoechst, and flow cytometry. TEM for mitochondrial morphology, MTT for cell proliferation ability, Western blot, and PCR were used to detect protein levels and mRNA changes. Sequencing analysis and cell experiments confirmed that TDB can promote the up-regulation of FOXO3 expression. TDB induced FOXO3 up-regulation in a dose-dependent manner, promoted the expression of p300 and Bim, and enhanced the acetylation and dephosphorylation of FOXO3, thus promoting apoptosis. p300 promotes apoptosis of cancer cells through Bim and other proteins, while HAT enhances the phosphorylation of FOXO3 and inhibits apoptosis. Overexpression of FOXO3 can increase the expression of exo-apoptotic pathways (FasL, TRAIL), endo-apoptotic pathways (Bim), and acetylation at the protein level and inhibit cell proliferation and apoptotic ability, while FOXO3 silencing or p300 mutation can partially reverse apoptosis. In tumor tissues with overexpression of FOXO3, TDB intervention can further increase the expression of p53 and caspase-9 proteins in tumor cells, resulting in loss of mitochondrial membrane integrity during apoptosis, the release of cytoplasm during signal transduction, activation of caspase-9 and synergistic inhibition of growth. TDB induces proliferation inhibition and promotes apoptosis of SMMC-7721 cells by activating p300-mediated FOXO3 acetylation. • FOXO3 was up-regulated after TDB intervention in hepatocellular carcinoma. • FOXO3 is a candidate therapeutic target for TDB to inhibit value-added and induce apoptosis. • Overexpression of FOXO3 significantly inhibited TDB proliferation and induced apoptosis in vivo/in vitro. [ABSTRACT FROM AUTHOR]

The anticancer activity of pectic polysaccharides (PPs) was proved by numerous studies, and which also indicated that the bioactivity of PPs was closely related to its complicated structures. Based on the summary and analysis about structure characteristics and corresponding enzymatic process of the reported PPs, the anticancer mechanism and related structural features were systematically clarified. It was found that not only the direct effects on the cancer cells by proliferation inhibition or apoptosis, but also the regulation of immune system, gut microbiota and gut metabolism as indirect effects, jointly played important roles in the anticancer of PPs. Nevertheless, during the study of PPs as promising anticancer components, the exact structure-function relationship, digestion process in vivo , and comprehensive action mechanism are still not well understanding. With the unveiling of the proposed issues, it is believed that PPs are promising to be exploited as effective cancer therapy/adjunctive therapy drugs or functional foods. [ABSTRACT FROM AUTHOR]

Apoptosis inhibition often leads to resistance to chemotherapeutics in bladder cancer (BC), resulting in poor prognosis of patients. Accumulating evidence suggests that induction of necroptosis, another type of programmed cell death, can be applied as an alternative strategy to kill apoptosis-insensitive BC cells. In this study, we showed that a novel Smac mimetic, ASTX660, also known as Tolinapant, can induce necroptosis in BC cells when apoptosis is inhibited. This is achieved by turning tumour necrosis factor (TNF)-α into a cytotoxic signal; ASTX660 then acts synergistically with TNF-α to induce necroptosis in BC cells. Mechanistic investigation showed that ASTX660 promoted the formation of the necrosome complex. Genetic or pharmacological inhibition of RIP1, RIP3, or MLKL, which are components of necrosome complex, provided protection against cell death induced by ASTX660 alone or ASTX660/TNF-α upon caspase inhibition. In addition, TNF-α/TNFR1 signalling and IRF1 are essential for the necroptosis induced by ASTX660 after the caspases are blocked. Our study highlights that ASTX660 can overcome the limitation of apoptosis induction via triggering necroptosis in BC cells. Therefore, our findings may provide some important clues for the design of a novel treatment strategy for BC. ∙ ASTX660 (Tolinapant), a novel smac mimetic, induces necroptosis in bladder cancer (BC) cells upon blockage of caspases. ∙ ASTX660 promotes the expression of TNF-α and cooperates with TNF-α to induce necroptosis in BC cells upon blockage of caspases. ∙ RIP1, RIP3 and MLKL are necessary for the necroptosis induced by ASTX660 or ASTX660/TNF-α upon blockage of caspases ∙ TNF-α/TNFR signalling and IRF1 are also essential for the necroptosis induced by ASTX660 or ASTX660/TNF-α upon blockage of caspases [ABSTRACT FROM AUTHOR]

Background: During the past few years, thyroid cancer (TC) has increased in terms of rate of morbidity and mortality. Plant flavonoids have shown positive effect in regulating thyroid tumorigenesis via inhibition of apoptosis. Robinin is a natural flavone glycoside isolated from Vinca erecta with potent pharmacological activities. Materials and Methods: In this study, we aimed to explore the apoptotic and cytotoxic activity of robinin against TPC-1 and SW1736 cells. Results: Robinin (20 μM/mL) significantly suppressed the growth and cell proliferation and induced apoptotic activity in TC cells. According to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, TPC-1 and SW1736 cancer cells revealed 100% cell viability. Robinin inhibited growth of TC cells in a dose-dependent manner. It was found that reactive oxygen species (ROS) generation in TPC-1 and SW1736 cancer cells was decreased; however, robinin (20 μM/mL) enhanced ROS formation. The study of apoptosis in TPC-1 and SW1736 cells revealed morphological changes and damaged nuclei. Robinin (20 μM/mL) triggered a powerful apoptosis signal and caused loss of membrane integrity in TC cells. It also increased the activity of caspases 8 and 9. Robinin (20 μM/mL) decreased the levels of Bcl-2, c-Myc, and cyclin-D1 and increased the levels of Bax and caspase-3 when compared to control and robinin-treated cells. It exhibited potent antiproliferative and apoptotic activity in TC cells. Conclusion: Robinin can be useful in the treatment of thyroid cancer. [ABSTRACT FROM AUTHOR]

The search for new cancer treatments from traditional medicine involves developing studies to understand at the molecular level different cell signaling pathways involved in cancer development. In this work, we present a model of the PI3K/Akt/mTOR pathway, which plays a key role in cell cycle regulation and is related to cell survival, proliferation, and growth in cancer, as well as resistance to antitumor therapies, so finding drugs that act on this pathway is ideal to propose a new adjuvant treatment. The aim of this work was to model, simulate and predict in silico using the Big Data-Cellulat platform the possible targets in the PI3K/Akt/mTOR pathway on which the Opuntia joconostle extract acts, as well as to indicate the concentration range to be used to find the mean lethal dose in in vitro experiments on breast cancer cells. The in silico results show that, in a cancer cell, the activation of JAK and STAT, as well as PI3K and Akt is related to the effect of cell proliferation, angiogenesis, and inhibition of apoptosis, and that the extract of O. joconostle has an antiproliferative effect on breast cancer cells by inhibiting cell proliferation, regulating the cell cycle and inhibiting apoptosis through this signaling pathway. In vitro it was demonstrated that the extract shows an antiproliferative effect, causing the arrest of cells in the G2/M phase of the cell cycle. Therefore, it is concluded that the use of in silico tools is a valuable method to perform virtual experiments and discover new treatments. The use of this type of model supports in vitro experimentation, reducing the costs and number of experiments in the real laboratory. [ABSTRACT FROM AUTHOR]

The present study aims to discover the influences of tamoxifen and 17β‐estradiol (E2) on tamoxifen‐resistant (TamR) patients in vitro. Herein, we established a stabilized TamR MCF‐7 cell line at 1 μM via gradient concentrations of tamoxifen cultivation. The expression changes of four ER subtypes (ERα66, ERβ, ERα36 and GPR30) were found to bring about tamoxifen resistance. Moreover, the generation of tamoxifen resistance involved in apoptosis escape via a reactive oxygen species‐regulated p53 signaling pathway. Interestingly, E2 at environmental concentrations (0.1–10 nM) could activate the expression of both ERα36 and GPR30, and then stimulate the phosphorylation of ERK1/2 and Akt, resulting in cell growth promotion. Cell migration and invasion promotion, apoptosis inhibition, and cell cycle G1‐S progression are involved in such proliferative effects. Conversely, the application of specific antagonists of ERα36 and GPR30 could restore tamoxifen's sensitivity as well as partially offset E2‐mediated proliferation. In short, overexpression of ERα36 and GPR30 not only ablate tamoxifen responsiveness but also could promote tumor progression of TamR breast cancer under estrogen conditions. These results provided novel insights into underlying mechanisms of tamoxifen resistance and the negative effects of steroid estrogens at environmental concentrations on TamR MCF‐7 cells, thus generating new thoughts for future management of ER‐positive breast cancer. [ABSTRACT FROM AUTHOR]

This document is a retraction notice for an article titled "MicroRNA-126 Inhibit Viability of Colorectal Cancer Cell by Repressing mTOR Induced Apoptosis and Autophagy." The authors of the article requested the retraction due to concerns about image duplication from unrelated articles. The authors were unable to provide original data or verify the validity of the reported findings. The retracted article will remain online but will be digitally watermarked as "Retracted." [Extracted from the article]

Neuronal nicotinic acetylcholine receptors containing the α9 or the α9 and α10 subunits are expressed in various extra-neuronal tissues. Moreover, most cancer cells and tissues highly express α9-containing receptors, and a number of studies have shown that they are powerful regulators of responses that stimulate cancer processes such as proliferation, inhibition of apoptosis, and metastasis. It has also emerged that their modulation is a promising target for drug development. The aim of this review is to summarize recent data showing the involvement of these receptors in controlling the downstream signaling cascades involved in the promotion of cancer. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Arsenic is a potent carcinogen in humans. However, the molecular mechanisms underlying its toxicity in lung cancer remain unclear. Here, we report that arsenite-induced cytotoxicity is regulated by SQSTM1/p62 and BNIP3L/Nix signaling in non-small-cell lung cancer H460 cells. Arsenite exposure resulted in dose-dependent growth inhibition, which was associated with apoptosis, as demonstrated by depolarized mitochondrial membrane potential and cleavage of caspase-8, caspase-3, PARP-1, and Bax. The autophagy adaptor p62 was detected in the monomeric and multiple high-molecular-weight (HMW) forms, and protein levels were upregulated depending on both arsenite concentrations (≤45 μM) and exposure times (<24 h). LC3-II, an autophagy marker, was upregulated as early as 1 h after arsenite treatment. Expression of Nix, a mitochondrial outer membrane protein, continued to increase with arsenite concentration and exposure time; it was detected in the monomeric and multiple HMW forms. Soon after arsenite exposure, p62 colocalized with Nix in the cytoplasm, and p62 knockdown reduced the Nix levels and increased the LC3-II levels. In contrast, Nix knockdown did not affect the p62 and LC3-II levels but reduced caspase-8, caspase-3, and Bax cleavage, indicating that Nix accumulation resulted from its reduced autophagic degradation and promoted apoptosis. p38 inhibition markedly increased arsenite-induced Nix protein and reduced p62 protein levels, resulting in increased autophagy and apoptosis. Furthermore, c-Jun NH 2 -terminal kinase inhibition reduced Nix and Bax cleavage, and both signaling pathways were suppressed by N -acetylcysteine treatment. Our results suggest that arsenite-induced cytotoxicity is modulated by the coordinated action of p62 and Nix through MAPK. • p62 protein levels depend on arsenite dose and exposure time. • Nix is upregulated with increasing arsenic dose and exposure time. • p62 regulates Nix protein localization and expression. • Arsenite induces autophagy and cleavage of procaspase-8 and Bax. • Arsenite cytotoxicity is modulated by p38-p62 and JNK-Nix signaling. [ABSTRACT FROM AUTHOR]

From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that facilitate survival and maintain their existence. Different kinds of stress stimuli trigger epigenetic alterations in cancer cells, which leads to changes in their transcriptome and metabolome, ultimately resulting in suppression of growth inhibition or induction of apoptosis. Whether cancer cells show a protective response to stress or succumb to cell death depends on the type of stress and duration of exposure. A thorough understanding of epigenetic and molecular architecture of cancer cell stress response pathways can unveil a plethora of information required to develop novel anticancer therapeutics. The present view highlights current knowledge about alterations in epigenome and transcriptome of cancer cells as a consequence of exposure to different physicochemical stressful stimuli such as reactive oxygen species (ROS), hypoxia, radiation, hyperthermia, genotoxic agents, and nutrient deprivation. Currently, an anticancer treatment scenario involving the imposition of stress to target cancer cells is gaining traction to augment or even replace conventional therapeutic regimens. Therefore, a comprehensive understanding of stress response pathways is crucial for devising and implementing novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) grades second among cancer-related deaths. Rehmanniae Radix (RR) has been exposed to have numerous pharmacological properties. Objectives: To inspect RR leaves extracts pro-apoptotic activities on SMMC-7721 liver cancer cell lines. Materials and Methods: Anti-cancer effect of RR extracts in SMMC-7721 liver cancer cell lines was aged rate of cell apoptosis (AO/EB, 4′,6-diamidino-2-phenylindole [DAPI], and PI staining), ΔΨm (Rh-123 staining), intracellular Reactive oxygen species (ROS) (DCFH-DA staining), quantitative polymerase chain reaction (mRNA expressions of Bax, p53, Bcl-2, caspase-3,-9,-8, IL-6, PI3K/AKT, and mTOR). Results: It has been shown that RR leaf ethanolic extracts suggestively declined cell viability, augmented the rate of cell apoptosis (AO/EB, DAPI, and PI staining), and caused the potential for ΔΨm, and induced over-accumulation of intracellular ROS (DCFH-DA staining) in SMMC-7721 cells after 24 h of exposure. In SMMC-7721 cell lines, we have examined anti-cancer activity to scrutinize the underlying mechanism by assessing the mRNA expressions of Bax, p53, Bcl-2, caspase-3,-9,-8, IL-6, PI3K/AKT, and mTOR. Results displayed the significant inhibition of the apoptosis as stated above related proteins. Conclusion: RR extracts exhibited its potential anti-cancer activity against SMMC-7721 cells by prompting apoptosis-induced cell death and inhibiting PI3K/AKT/mTOR signaling. [ABSTRACT FROM AUTHOR]

Alternative polyadenylation (APA) is an important RNA post-transcriptional process, which can generate diverse mRNA isoforms. Increasing evidence shows that APA is involved in cell self-renewal, development, immunity, and cancer. CPSF6 is one of the core proteins of CFIm complex and can modulate the APA process. Although it has been reported to play oncogenic roles in cancer, the underlying mechanisms remain unclear. The aim of the present study was to characterize CPSF6 in human gastric cancer (GC). We observed that CPSF6 was upregulated in GC. Knockdown of CPSF6 inhibited proliferation and enhanced apoptosis of GC cells both in vitro and in vivo. Global APA site profiling analysis revealed that knockdown of CPSF6 induced widespread 3′UTR shortening of genes in GC cells, including VHL. We also found CPSF6 negatively regulated the expression of VHL through APA and VHL short-3′UTR isoform enhanced apoptosis and inhibited cell growth in GC cells. Our data suggested that CPSF6-induced cell proliferation and inhibition of apoptosis were mediated by the preferential usage of poly(A) in VHL. Our data provide insights into the function of CPSF6 and may imply potential therapeutic targets against GC. [ABSTRACT FROM AUTHOR]

Background: Propolis is a resinous product accumulated from several plant sources that possess a wide range of therapeutic properties, including anti-cancer activities. However, the role of honeybee-produced propolis on head and neck squamous carcinoma (HNSCC) is not well understood. The aim of this study was to investigate the effects of Apis mellifera propolis on apoptosis and invasiveness in HNSCC cell lines. Methods: Ethyl acetate extract of propolis (EAEP) was prepared from A. mellifera beehives using liquid–liquid extraction. High-performance liquid chromatography coupled with electrospray ionization-time of flight-mass spectrometry (HPLC-ESITOF-MS) was used to determine the flavonoids in EAEP. Isogenic HNSCC cell lines derived from primary (HN30 and HN4) and metastatic site (HN31 and HN12) were used in this study. The cytotoxicity, apoptosis, invasion, and MMP activity of EAEP on HNSCC cells were determined using an MTT assay, flow cytometry, Matrigel invasion assay, and gelatinase zymography, respectively. Results: We found that EAEP exhibited cytotoxic activity and induced apoptosis in the HNSCC cell lines. Furthermore, EAEP significantly decreased HNSCC cell invasion by reducing MMP-2 and MMP-9 activity. Two flavonoids, galangin and apigenin, were identified in EAEP by HPLC-ESI-TOF-MS. The results suggest that EAEP promotes apoptosis and exerts anti-invasion potential by inhibiting MMP-2 and MMP-9 activity in HNSCC cell lines. These inhibitory effects may be mediated by galangin and apigenin [ABSTRACT FROM AUTHOR]

Translational control (TC) is one the crucial steps that dictate gene expression and alter the outcome of physiological process like programmed cell death, metabolism, and proliferation in a eukaryotic cell. TC occurs mainly at the translation initiation stage. The initiation factor eIF5B tightly regulates global translation initiation and facilitates the expression of a subset of proteins involved in proliferation, inhibition of apoptosis, and immunosuppression under stress conditions. eIF5B enhances the expression of these survival proteins to allow cancer cells to metastasize and resist chemotherapy. Using eIF5B as a biomarker or drug target could help with diagnosis and improved prognosis, respectively. To achieve these goals, it is crucial to understand the role of eIF5B in translational regulation. This review recapitulates eIF5B's regulatory roles in the translation initiation of viral mRNA as well as the cellular mRNAs in cancer and stressed eukaryotic cells. [ABSTRACT FROM AUTHOR]

Objectives In this study, we sought to evaluate purpurin, a natural biomedicine and a potential inhibitor in decreasing the growth rate of lung cancer cells by modulating the role of PI3K/AKT signalling-associated proliferation and apoptosis. Methods A549 cells were treated with purpurin (30 μM) for 24 and 48 h incubation, respectively, and it has been analysed for cytotoxicity, ROS-mediated apoptotic staining. Moreover, purpurinmediated lipid peroxidation and GSH were measured by biochemical estimation. Furthermore, PI3K/AKT signalling-mediated cell proliferation and apoptotic gene expression done were by western blot. Key findings In this study, we observed that purpurin could effectively kill A549 cancer cell lines and leads to cell death, thus conforming increased cytotoxicity, production of ROS-mediated enhancement of lipid peroxidation, nuclear fragmentation and apoptosis. Moreover, the GSH content of A549 cell lines was also diminished after treatment with purpurin. This study demonstrates that purpurin inhibits the phosphorylated PI3K/AKT molecules mediated cyclin-D1 and PCNA, thereby inducing apoptosis by observing increased proapoptotic mediators Bax, cleaved PARP, cytochrome-c, caspase-9 and caspase-3; and decreased Bcl-2 expression in the lung cancer cell lines. Conclusion This result concluded that purpurin eliminates the A549 lung cancer cells by blocking the PI3K/AKT pathway thereby inducing apoptosis. [ABSTRACT FROM AUTHOR]

This work investigated the effect of α‐mangostin (α‐M) on gastric cancer (GC) cell chemoresistance and its underlying mechanisms. Different concentrations of α‐M and CDDP were applied to treat GC cells (SGC7901) and CDDP‐resistant GC cells (SGC7901/CDDP) for 24 or 48 h. CCK‐8 assays were used to measure the inhibitory effect of CDDP or α‐M on SGC7901 and SGC7901/CDDP cells as well as the half‐maximal inhibitory concentrations (IC50) of α‐M for SGC7901 and SGC7901/CDDP cells. The optimal concentration and induction time of CDDP or α‐M were determined. SGC7901/CDDP cells were treated with CDDP or/and α‐M, where some of them were transfected with pcDNA3.1 or pcDNA3.1‐EBI3. Cell proliferation and apoptosis were assessed as well as the levels of EBI3, STAT3, p‐STAT3, autophagy‐related proteins, and apoptosis‐related proteins. CDDP inhibited SGC7901 cell proliferation in a dose‐dependent manner. The IC50 of α‐M for SGC7901 cells was 12.86 μM and that for SGC7901/CDDP cells was 13.69 μM. The optimal concentrations of CDDP and α‐M for SGC7901/CDDP cells were 2 and 15 μM, respectively, and the optimal time was 48 h. The SGC7901/CDDP cells in the CDDP+/α‐M+ group had elevated inhibition of proliferation and apoptosis rates. Western blot analysis revealed enhanced levels of LC3‐II/I and Beclin1, reduced p62 level, decreased Bcl2 level, and increased levels of Bax and cleaved caspase‐3/9. The EBI3/STAT3 pathway was implicated in the effect of α‐M on SGC7901/CDDP cell development. α‐M increases the chemosensitivity of GC cells by facilitating autophagy and inactivating the EBI3/STAT3 pathway. [ABSTRACT FROM AUTHOR]

The dynamics of tumors growth and associated events cover multiple time and spatial scales, generally including extracellular, cellular and intracellular modifications. The main goal of this study is to model the biological and physical behavior of tumor evolution in presence of normal healthy tissue, taking in consideration a variety of events involved in the process. These include hyper and hypoactivation of signaling pathways during tumor growth, vessels growth, intratumoral vascularization and competition of cancer cells with healthy host tissue. The work addresses two distinctive phases in tumor development—the avascular and vascular phases—and in each stage two cases are considered—with and without normal healthy cells. The tumor growth rate increases considerably as closed vessel loops (anastomoses) form around the tumor cells resulting from tumor induced vascularization. When taking into account the host tissue around the tumor, the results show that competition between normal cells and cancer cells leads to the formation of a hypoxic tumor core within a relatively short period of time. Moreover, a dense intratumoral vascular network is formed throughout the entire lesion as a sign of a high malignancy grade, which is consistent with reported experimental data for several types of solid carcinomas. In comparison with other mathematical models of tumor development, in this work we introduce a multiscale simulation that models the cellular interactions and cell behavior as a consequence of the activation of oncogenes and deactivation of gene signaling pathways within each cell. Simulating a therapy that blocks relevant signaling pathways results in the prevention of further tumor growth and leads to an expressive decrease in its size (82% in the simulation). Author summary: Mathematical modeling and simulation of cancer across different biological scales is becoming increasingly important in the development of therapeutic strategies. In the current work, a multiscale model is presented to study the growth and progression of tumor and angiogenesis based on tumor-host interactions which allows to investigate the effects of tumor- targeted therapy. Considering the signal-transduction networks involved in various types of cancers, we proposed a cascade that encompasses some significant signaling pathways. A Boolean network model is employed to describe the receptors cross-talk. As a result of the activation of oncogenes and deactivation of pertinent gene signaling pathways within each cell, the cellular interactions and cell behavior are modeled. By linking cells state with environmental cues, the tumor morphology is determined. Consistent with the experimental observations, the intratumoral vascularization density resulting from the simulation reports malignancy grade as a prognostic parameter. Moreover, our model permits to explore possible novel therapeutic procedures, including therapies targeting specific pathways. It captures cellular apoptosis by receptor inhibition in tumor development as a new area of mathematical modeling of targeted therapy. [ABSTRACT FROM AUTHOR]

The incidence of bladder cancer in traditional green tea‐consuming countries was dramatically lower than low green tea‐consuming countries. Epigallocatechin‐3‐gallate (EGCG), an active ingredient extracted from green tea, showed effective inhibition of formation and progression of many tumors. However, whether autophagy involved in this tumor‐suppression mechanism of EGCG on bladder cancer was still unclear. In this study, we demonstrated low concentration of EGCG‐induced proliferation inhibition and increased apoptosis in bladder cancer cell lines (5,637 and T24 cells) indicated by the increased expression of apoptosis‐related protein (caspase9, caspase3 and BAX). In addition, low dose of EGCG also regulated autophagy pathway associated protein (LC3B II and Beclin) expression and this autophagy pathway was blocked by PI3K/AKT inhibitor; moreover, knockdown of ATG5 reversed EGCG‐induced apoptosis in 5,637 cells, indicating that EGCG might inhibit the bladder cancer through autophagy pathway. Our findings indicated that EGCG should be considered as a novel therapy for bladder cancer treatment by regulating autophagy pathway. Practical applications: Our research proved EGCG from green tea could be used as an effective anti‐tumor ingredient by revealing another mechanism that epigallocatechin‐3‐Gallate inhibited bladder cancer cells via inducing autophagy‐related apoptosis. And green tea could be considered as a kind of tumor‐preventing beverage. [ABSTRACT FROM AUTHOR]

To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells. Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1). High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients. The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor. [ABSTRACT FROM AUTHOR]

Lung cancer is a leading cause of cancer‐related death worldwide. In this study, we used lung adenocarcinoma cells as a model, as lung adenocarcinoma has the highest mortality rate among all lung cancers. For the past few years, medical treatments or lung cancer have been limited because of chemotherapy resistance. Therefore, understanding the pathogenesis of the development of drug resistance in lung cancer is urgent. Gemcitabine is widely prescribed in the chemotherapeutic treatment of lung cancers. In this study, we developed gemcitabine‐resistant lung adenocarcinoma cells (A549‐GR) from the A549 cell line. The results showed that apoptotic protein expression and reactive oxygen species (ROS) generation were reduced in A549‐GR cells compared to A549 cells. Interestingly, we found that signal transducer and activator of transcription 3 (STAT3) translocated to the nucleus and mitochondria to affect the apoptotic pathway and ROS generation, respectively. Furthermore, treatment with STAT3 small interfering RNA diminished the increase in ROS production, proliferation and antiapoptotic proteins in A549‐GR cells. Taken together, the study demonstrated that STAT3 acts as an essential regulator and moderates apoptosis through two major mechanisms to induce gemcitabine resistance in cells; and these findings provide a potential target for the treatment of gemcitabine‐resistant lung cancer. [ABSTRACT FROM AUTHOR]

The incidence of malignant melanoma, a neoplasm of melanocytic cells, is increasing rapidly. The lymph nodes are often the first site of metastasis and can herald systemic dissemination, which is almost uniformly fatal. RLIP, a multi-specific ATP-dependent transporter that is over-expressed in several types of cancers, plays a central role in cancer cell resistance to radiation and chemotherapy. RLIP appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that the depletion or inhibition of RLIP causes selective toxicity to malignant cells. RLIP depletion/inhibition triggers apoptosis in cancer cells by inducing the accumulation of endogenously formed glutathione-conjugates. In our in vivo studies, we administered RLIP antibodies or antisense oligonucleotides to mice bearing subcutaneous xenografts of SKMEL2 and SKMEL5 melanoma cells and demonstrated that both treatments caused significant xenograft regression with no apparent toxic effects. Anti-RLIP antibodies and antisense, which respectively inhibit RLIP-mediated transport and deplete RLIP expression, showed similar tumor regressing activities, indicating that the inhibition of RLIP transport activity at the cell surface is sufficient to achieve anti-tumor activity. Furthermore, RLIP antisense treatment reduced levels of RLIP, pSTAT3, pJAK2, pSrc, Mcl-1 and Bcl2, as well as CDK4 and cyclin B1, and increased levels of Bax and phospho 5' AMP-activated protein kinase (pAMPK). These studies indicate that RLIP serves as a key effector in the survival of melanoma cells and is a valid target for cancer therapy. Overall, compounds that inhibit, deplete or downregulate RLIP will function as wide-spectrum agents to treat melanoma, independent of common signaling pathway mutations. [ABSTRACT FROM AUTHOR]

During the early phase of tumorigenesis, primary malignant cells survive within a low nutrition environment caused by a poorly organized vascular system. Here, we sought to determine the functional significance of CD133 in the survival of cancer cells under nutrient‐poor conditions. Knockdown and overexpression experiments demonstrated that CD133 suppresses colon cancer cell death induced by serum deprivation through activation of Akt‐mediated anti‐apoptosis and protein synthesis pathways. Furthermore, serum deprivation increased the amount of endogenous CD133 protein, which was regulated at least in part by phosphoinositide 3‐kinase. Thus, it is highly likely that CD133 contributes to the acquisition/maintenance of the resistance to stress arising from nutrient deficiency in early avascular tumor tissues. [ABSTRACT FROM AUTHOR]

The thyroid cancer, especially papillary thyroid cancers are very common among population with high intake of iodine or iodine uptake. Even though several treatment options are available, there is still complication and side effects are still persistent. The role of signaling molecules in cancer signaling is very vast and their significance in progression of disease was increasing which leads to mortality of the patient. The major key players are PI3K, AKT and MAP kinase, involves in cell survival, proliferation, and inhibition of apoptosis and are the promising candidate for cancer treatment target, several researchers focuses these molecule to treat various acute and chronic diseases like cancer. On the other side, various literatures propose that natural compounds derived from plant source are shown potent anticancer property against several cancers. In our study we are looking in to one such active principle obtained from plant source, a diterpenoid compound kirenol, and its role thyroid cancer. Here, we report that kirenol role on various cellular mechanisms like induction of apoptosis, enhancing ROS indirectly by inhibiting antioxidants, altering the signaling mechanism of cell survival and apoptosis. Our study proposes that kirenol involved in the cancer cell cytotoxicity by inducing apoptosis and inhibition of cancer cell survival. Thus, targeting this signaling molecule with kirenol definitely favors and may lead to a therapeutic modality for thyroid cancer. [ABSTRACT FROM AUTHOR]

Non‐small‐cell lung cancer (NSCLC) is the most frequent cause of cancer‐related death. In this study, we found the anticancer activity of lotus seedpod extract (LSPE) in NSCLC cells, since LSPE treatment inhibited cell proliferation of A549 and H460 cells in a dose‐dependent manner and the clonogenic activities of LSPE‐treated cells were also reduced. In LSPE‐treated cells, the cleavage of poly (ADP‐ribose) polymerase (PARP) and phosphorylation of H2X, were also observed, indicating the pro‐apoptotic effect of LSPE. Next, we found that LPSE treatment diminished the levels of protein and mRNA of Axl, a receptor tyrosine kinase (RTK) that transduces critical signals for cell proliferation and inhibition of apoptosis. The promoter activity of Axl was found to be dose‐dependently decreased in response to LSPE treatment, implying that LSPE inhibited Axl gene expression at transcriptional level. In addition, Axl overexpression was found to decrease the effects of LSPE on inhibition of cell proliferation and colony formation as well as induction of PARP cleavage and phosphorylation of H2AX, while the same activities of LPSE were increased by knockdown of Axl gene expression, indicating that the antiproliferative and pro‐apoptotic effect of LSPE is inversely proportional to the protein level of Axl. Taken together, we found that the LSPE suppressed cell proliferation and induced apoptosis of NSCLC cells, which is attenuated or augmented by overexpression or RNA interference of Axl expression, respectively. Our data suggest that Axl is a novel therapeutic target of LSPE to inhibit cell proliferation and promote apoptosis in NSCLC cells. Practical applications: In this study, lotus seedpod extract (LSPE) was found to have the cytotoxic and apoptosis‐inducing potentials in non‐small‐cell lung cancer (NSCLC) cells. LSPE downregulated the Axl expression at transcriptional level and the effects of LSPE on cell proliferation as well as apoptosis were affected by Axl protein level. Therefore, the inference of Axl‐mediated intracellular signals by LSPE must be a novel approach to control NSCLC. Since our data imply that LSPE contains bioactive compounds targeting Axl, further studies to elucidate these compounds might discover a potent therapeutic agent. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM), a malignancy of plasma cells, is the second most prevalent hematological cancer. Bortezomib is the most effective chemotherapeutic drug used in treatment. However, drug-resistance prevents success of chemotherapy. One of the factors causing drug-resistance is dysfunction of apoptotic-pathways. This study aimed to evaluate the relationship between expression levels of Bcl-2, Bax, caspase-3 and p-53 genes involved in apoptosis and the development of bortezomib-resistance in MM cell lines. Materials and methods: Multiple myeloma KMS20 (bortezomib-resistant) and KMS28 (bortezomib-sensitive) cell lines were used. 3-[4,5-Dimethylthiazol-2-yl] 1-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine IC50 values of bortezomib. RNAs were isolated from bortezomib-treated cell lines, followed by cDNA synthesis. Expression levels of the genes were analyzed by using q-Realtime-PCR. Results: As a result, Bcl-2/Bax ratio was higher in KMS20 (resistant) cells than in KMS28 (sensitive) cells. Expression of caspase-3 decreased in KMS20-cells, whereas increased in KMS28-cells. The results indicate that apoptosis was suppressed in resistant cells. Conclusion: These findings will enable us to understand the molecular mechanisms leading to drug-resistance in MM cells and to develop new methods to prevent the resistance. Consequently, preventing the development of bortezomib resistance by eliminating the factors which suppress apoptosis may be a new hope for MM treatment. [ABSTRACT FROM AUTHOR]

Long intergenic noncoding RNAs (lincRNAs) play a vital role in the occurrence and progression of cancer. The mechanism of lincRNAs in colorectal cancer (CRC) has not been fully elucidated. In this context, an integrated comparative long noncoding RNA (lncRNA) microarray technology was used to determine the expression profile of lncRNAs in CRC. The roles of LINC00908 are unclear. We found that LINC00908 was significantly upregulated in CRC. Inhibition of LINC00908 resulted in reduced cell proliferation and G1 cell cycle arrest, which was mediated by cyclin D1, cyclin‐dependent kinase 4, and phosphorylated retinoblastoma. Moreover, inhibition of LINC00908‐induced apoptosis through the intrinsic apoptosis signaling pathway, as shown by the activation of caspase‐9 and caspase‐3. Mechanistically, miR‐143‐3p directly bound to LINC00908. miR‐143‐3p expression was negatively correlated with LINC00908 expression in CRC tissue. Functional experiments revealed opposing roles for miR‐143‐3p and LINC00908, suggesting that LINC00908 negatively regulates miR‐143‐3p. Mechanistically, miR‐143‐3p directly targets LINC00908. The KLF5 inhibitor ML264 affected proliferation and apoptosis, indicating that LINC00908 may act as a competing endogenous RNA to facilitate the expression of the miR‐143‐3p target gene KLF5. Thus, LINC00908 has an important proliferative and antiapoptotic role in CRC by regulating the cell cycle and intrinsic apoptosis. LINC00908 could be a potential biomarker and a new therapeutic target for CRC. [ABSTRACT FROM AUTHOR]