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Gambogic acid (GA) inhibits the proliferation of various human cancer cells. However, because of its water insolubility, the antitumor efficacy of GA is limited. Objectives. To investigate the antitumor activity of gambogic acid lysinate (GAL) and its mechanism. Methods. Inhibition of cell proliferation was determined by MTT assay; intracellular ROS level was detected by staining cells with DCFH-DA; cell apoptosis was determined by flow cytometer and the mechanism of GAL was investigated by Western blot. Results. GAL inhibited the proliferation of MCF-7 cells with IC50 values 1.46 µmol/L comparable with GA (IC50, 1.16 µ mol/L). GAL promoted the production of ROS; however NAC could remove ROS and block the effect of GAL. GAL inhibited the expression of SIRT1 but increased the phosphorylation of FOXO3a and the expression of p27Kip1. At knockdown of FOXO3a, cell apoptosis induced by GAL can be partly blocked. In addition it also enhanced the cleavage of caspase-3. Conclusions. GAL inhibited MCF-7 cell proliferation and induced MCF-7 cell apoptosis by increasing ROS level which could induce cell apoptosis by both SIRT1/FOXO3a/p27Kip1 and caspase-3 signal pathway. These results suggested that GAL might be useful as a modulation agent in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Pyroptosis is a type of programmed cell death and plays a dual role in distinct cancers. It is elusive to evaluate the activation level of pyroptosis and to appraise the involvement of pyroptosis in the occurrence and development of diverse tumors. Accordingly, we herein established an indicator to evaluate pyroptosis related gene transcription levels based on the expression level of genes involved in pyroptosis and tried to elaborated on the association between pyroptosis and tumors across diverse tumor types. We found that pyroptosis related gene transcription levels could predict the prognosis of patients, which could act as either a favorable or a dreadful factor in diverse cancers. According to signaling pathway analyses we observed that pyroptosis played a significant role in immune regulation and tumorigenesis and had strong links with other forms of cell death. We also performed analysis on the crosstalk between pyroptosis and immune status and further investigated the predictive potential of pyroptosis level for the efficacy of immunotherapy. Lastly, we manifested that pyroptosis status could serve as a biomarker to the efficacy of chemotherapy across various cancers. In summary, this study established a quantitative indicator to evaluate pyroptosis related gene transcription levels, systematically explored the role of pyroptosis in pan-cancer. These results could provide potential research directions targeting pyroptosis, and highlighted that pyroptosis may be used to develop a novel strategy for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Pyroptosis is a type of programmed cell death and plays a dual role in distinct cancers. It is elusive to evaluate the activation level of pyroptosis and to appraise the involvement of pyroptosis in the occurrence and development of diverse tumors. Accordingly, we herein established an indicator to evaluate pyroptosis related gene transcription levels based on the expression level of genes involved in pyroptosis and tried to elaborated on the association between pyroptosis and tumors across diverse tumor types. We found that pyroptosis related gene transcription levels could predict the prognosis of patients, which could act as either a favorable or a dreadful factor in diverse cancers. According to signaling pathway analyses we observed that pyroptosis played a significant role in immune regulation and tumorigenesis and had strong links with other forms of cell death. We also performed analysis on the crosstalk between pyroptosis and immune status and further investigated the predictive potential of pyroptosis level for the efficacy of immunotherapy. Lastly, we manifested that pyroptosis status could serve as a biomarker to the efficacy of chemotherapy across various cancers. In summary, this study established a quantitative indicator to evaluate pyroptosis related gene transcription levels, systematically explored the role of pyroptosis in pan-cancer. These results could provide potential research directions targeting pyroptosis, and highlighted that pyroptosis may be used to develop a novel strategy for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Embryo implantation is essential for normal pregnancy, and the process of decidualization is critical for embryo implantation. However, the mechanism of decidualization during early pregnancy is still unknown. Forkhead box O3a (FOXO3a) is the most important functional transcription factor of the forkhead box family and is a highly conserved transcription factor of apoptosis‐related genes. In the mouse uterus, FOXO3a was found to be expressed regularly from Days 1–7 of early pregnancy. Upon further exploration, it was found that FOXO3a was expressed at significantly higher levels at the implantation site than at the interimplantation site on Days 5–7 of pregnancy. Under artificial decidualization, FOXO3a was highly expressed in the first and second decidual zones. After decidualization, the expression of FOXO3a was significantly increased both in vivo and vitro. In primary stromal cells, apoptosis was reduced by decreased expression of FOXO3a after inducing decidualization. Moreover, when FOXO3a‐small interfering RNA was transfected into the uteri of mice, the expression of decidualization‐ and apoptosis‐related factors was impaired. Thus, FOXO3a might play an important role in decidualization during early pregnancy, and cell apoptosis might be one of pathways for FOXO3a‐regulated decidualization. Embryo implantation is essential for normal pregnancy, and the process of decidualization is critical for embryo implantation. The expression of forkhead box O3a (FOXO3a) was significantly increased when decidualization both in vivo and vitro. FOXO3a might play an important role in decidualization during early pregnancy. [ABSTRACT FROM AUTHOR]

Wild-type p53-induced phosphatase (Wip1) is a member of the protein phosphatase type 2C family and is an established oncogene due to its dephosphorylation of several tumor suppressors and negative control of the DNA damage response system. It has been reported to dephosphorylate p53, ataxia telangiectasia mutated, checkpoint kinase 1 and p38 mitogen activated protein kinases, forming negative feedback loops to inhibit apoptosis and cell cycle arrest. Wip1 serves a major role in tumorigenesis, progression, invasion, distant metastasis and apoptosis in various types of human cancer. Therefore, it may be a potential biomarker and therapeutic target in the diagnosis and treatment of cancer. Furthermore, previous evidence has revealed a new role for Wip1 in the regulation of chemotherapy resistance. In the present review, the current knowledge on the role of Wip1 in cancer is discussed, as well as its potential as a novel target for cancer treatment and its function in chemotherapy resistance. [ABSTRACT FROM AUTHOR]

Backgound: The mechanistic target of rapamycin complex 1 (mTORC1) is important in the development and progression of many cancers. Targeted cancer therapy using mTORC1 inhibitors is used for treatment of cancers; however, their clinical efficacies are still limited.Methods: We recently created a new mouse model for human lymphangiosarcoma by deleting Tsc1 in endothelial cells and consequent hyper-activation of mTORC1. Using Tsc1iΔEC tumour cells from this mouse model, we assessed the efficacies of histone deacetylase (HDAC) inhibitors as anti-tumour agents for mTORC1-driven tumours.Results: Unlike the cytostatic effect of mTORC1 inhibitors, HDAC inhibitors induced Tsc1iΔEC tumour cell death in vitro and their growth in vivo. Analysis of several HDAC inhibitors suggested stronger anti-tumour activity of class I HDAC inhibitor than class IIa or class IIb inhibitors, but these or pan HDAC inhibitor SAHA did not affect mTORC1 activation in these cells. Moreover, HDAC inhibitor-induced cell death required elevated autophagy, but was not affected by disrupting caspase-dependent apoptosis pathways. We also observed increased reactive oxygen species and endoplasmic reticulum stress in SAHA-treated tumour cells, suggesting their contribution to autophagic cell death, which were dependent on mTORC1 hyper-activation.Conclusion: These studies suggest a potential new treatment strategy for mTORC1-driven cancers like lymphangiosarcoma through an alternative mechanism. [ABSTRACT FROM AUTHOR]

Cover: The cover image, by Long et al., is based on the Original Research Article, FOXO3a is essential for murine endometrial decidualization through cell apoptosis during early pregnancy, DOI: 10.1002/jcp.27167. [ABSTRACT FROM AUTHOR]

Loss of sirtuin 1 (SIRT1) activity may be associated with metabolic diseases, including diabetes. The aim of the present study was to investigate the potential effects of overexpressed endothelial nitric oxide synthase (eNOS) on cell proliferation and apoptosis with SIRT1 activation in the Min6 mouse pancreatic ß cell line. A pcDNA3.0-eNOS plasmid was constructed and transfected into Min6 cells for 24 h prior to harvesting. eNOS expression was validated and SIRT1 expression was detected following plasmid transfection using reverse transcription-quantitative polymerase chain reaction and western blot analysis, which demonstrated that the expression levels of eNOS and SIRT1 were significantly upregulated. Furthermore, the cell proliferation and cell apoptosis of the Min6 cells were evaluated, using a cell counting kit-8 assay and flow cytometry, respectively. The results suggested that overexpressed eNOS promoted cell proliferation and inhibited cell apoptosis in Min6 cells. The interaction between eNOS and SIRT1 was explored through co-immunoprecipitation, and it found that there was a strong interaction between eNOS and SIRT1. In conclusion, overexpressed eNOS may induce SIRT1 activation, which is implied to play a protective role in Min6 cells, and eNOS may be a new therapeutic target for diseases such as type 2 diabetes. [ABSTRACT FROM AUTHOR]

Purpose: To formulate trimethyl chitosan-functionalized retinoic acid-encapsulated solid lipid nanoparticles for the effective treatment of glioma. Methods: Retinoic acid-loaded solid lipid nanoparticles (R-SLNs) were prepared using homogenization followed by sonication. R-SLN surfaces were functionalized electrostatically with trimethyl chitosan as a nanocarrier (TR-SLNs) with enhanced anti-cancer activity. They were evaluated by dynamic light scattering (DLS), scanning electron microscopy, in vitro drug release, and cell cytotoxicity and apoptosis studies. Results: Morphological images showed spherical and uniformly dispersed nanoparticles. A sustained monophasic release pattern was observed throughout the study period. Furthermore, the anti-cancer effect of TR-SLNs was demonstrated by increased cell killing activity compared with the free drug (p < 0.01); negligible cytotoxicity was observed with blank carriers. Apoptosis assay showed increased cell populations in early/late apoptotic and necrotic phases. Conclusion: This study showed the potential application of surface-modified solid lipid nanoparticles for the effective treatment of brain cancer. [ABSTRACT FROM AUTHOR]

We characterised DNA methylation and gene expression of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4, DR5, DcR1 and DcR2 in three choriocarcinoma (JAR, JEG-3, BeWo) and two transformed (HTR-8/SVneo and HPT-8) cell lines. DR4 mRNA was detected in JAR, JEG-3, BeWo and HTR-8/SVneo cells, whereas DR5 was present in all detected cells. DcR1 transcripts were expressed only in JAR, JEG-3 and BeWo cells, whereas DcR2 transcripts were detected only in HTR-8/SVneo and HPT-8 cells. Hypermethylated DR4 promoter was observed in JAR, JEG-3, BeWo and HTR-8/SVneo cells, hypermethylated DcR1 promoter in HTR-8/SVneo and HPT-8 cells and hypermethylated DcR2 promoter in JAR, JEG-3 and BeWo cells. Restoration of DR4, DcR1 and DcR2 expression with decreased DNA methylation of these genes was induced by the DNA demethylation agent 5-aza-2'-deoxycytidine (5-aza-CdR) in trophoblast cells, whereas DR5 expression did not exhibit any change. Significant negative correlation between the expression and DNA methylation of these genes was also observed. In all tested cell lines, only HPT-8 demonstrated sensitivity to TRAIL-induced apoptosis. Combined treatment with 5-aza-CdR and TRAIL resulted in apoptosis in JAR, JEG-3, BeWo and HTR-8/SVneo cells but not in HPT-8 cells. The results indicate that DNA methylation is associated with TRAIL receptor expression and might be involved in trophoblast apoptosis. [ABSTRACT FROM AUTHOR]

Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, is widely used in metastatic bone disease. Previous studies indicate that ZOL has marked anti-leukemia activity, however, the underlying mechanism of action remains to be elucidated. The present study aimed to explore the mechanism of the anti-leukemia effect of ZOL in leukemia cells. It was observed that ZOL inhibited the proliferation of HL-60 and adriamycin-resistant HL-60 (HL-60/A) cells using a WST-8 assay. An Annexin V-propidium iodide indicated that ZOL induced apoptosis of the two cell types in a dose- and time-dependent manner. Hoechst 33342 staining was also used to verify the levels of apoptosis. The colony formation assay demonstrated that ZOL significantly inhibited colony formation capacity in acute myeloid leukemia (AML) cells. This was achieved by the induction of S-phase cell cycle arrest, downregulation of B-cell lymphoma 2 (Bcl-2) and upregulation of Bcl-2 associated X protein and cleaved poly (ADP-ribose) polymerase. The results indicate that ZOL inhibited cell proliferation by inducing apoptosis via the mitochondrial apoptotic pathway and this anti-leukemic activity appeared notably enhanced in HL-60/A cells. As ZOL is already available for clinical use, these results indicate that it may be an effective addition to the chemotherapeutic strategies for AML. [ABSTRACT FROM AUTHOR]

Background: Chronic myelogenous leukemia (CML) is a hematological stem cell disorder. Tyrosine kinase inhibitors (TKIs) are the standard treatments for CML, but a number of patients fail to respond effectively due to gene mutations. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to have anti-tumor effect on solid tumor whereas the anti-CML effect and its underlying mechanism have not been completely elucidated.Methods: The cytotoxic effects of celecoxib and/or imatinib were evaluated by MTT assay. Cell cycle distribution was examined by propidium iodide (PI) assay. Apoptosis or necrosis was analyzed by Annexin-V/PI, Hoechst 33342 staining and Western blot assays. Autophagy suppression effect of celecoxib was examined by Western blot and LysoTracker probe labelling. Lysosensor probe labelling was used to detect the effect of celecoxib on the lysosomal function.Results: In this study, we found that celecoxib had therapy efficacy in KBM5 and imatinib-resistant KBM5-T315I CML cell lines. Celecoxib caused significant cytotoxic effect in both cell lines, especially in KBM5-T315I cells exposed to celecoxib for 72 h. Moreover, celecoxib induced necrosis and apoptosis while inhibited autophagy in CML cell lines and patient samples. Furthermore, this study demonstrated that celecoxib prevented the autophagic flux by inhibiting lysosome function. Celecoxib was tested in combination with imatinib, demonstrating that celecoxib could strengthen the cytotoxicity of imatinib in imatinib-resistant CML cells.Conclusions: These findings showed that celecoxib had therapy efficacy on CML cells. And it is first time to demonstrate that celecoxib is an autophagy suppresser and a combination of celecoxib and imatinib might be a promising new therapeutic strategy for imatinib-resistant CML cells. [ABSTRACT FROM AUTHOR]

Previous studies have reported that mTORC2 promotes cell survival through phosphorylating AKT and enhancing its activity. We reveal another mechanism by which mTORC2 controls apoptosis. Inactivation of mTORC2 promotes binding of CIP2A to PP2A, leading to reduced PP2A activity toward c-Myc serine 62 and, consequently, enhancement of c-Myc phosphorylation and expression. Increased c-Myc activity induces transcription of pri-miR-9-2/miR-9-3p, in turn inhibiting expression of E2F1, a transcriptional factor critical for cancer cell survival and tumor progression, resulting in enhanced apoptosis. In vivo experiments using B cell-specific mTORC2 (rapamycin-insensitive companion of mTOR) deletion mice and a xenograft tumor model confirmed that inactivation of mTORC2 causes up-regulation of c-Myc and miR-9-3p, down-regulation of E2F1, and consequent reduction in cell survival. Conversely, Antagomir-9-3p reversed mTORC1 /2 inhibitor-potentiated E2F1 suppression and resultant apoptosis in xenograft tumors. Our in vitro and in vivo findings collectively demonstrate that mTORC2 promotes cell survival by stimulating E2F1 expression through a c-Myc-and miR-9-3p-dependent mechanism. [ABSTRACT FROM AUTHOR]

Autophagy is an evolutionarily conserved cellular process controlled through a set of essential autophagy genes (Atgs). However, there is increasing evidence that most, if not all, Atgs also possess functions independent of their requirement in canonical autophagy, making it difficult to distinguish the contributions of autophagy-dependent or -independent functions of a particular Atg to various biological processes. To distinguish these functions for FIP200 (FAK family-interacting protein of 200 kDa), an Atg in autophagy induction, we examined FIP200 interaction with its autophagy partner, Atg13. We found that residues 582-585 (LQFL) in FIP200 are required for interaction with Atg13, and mutation of these residues to AAAA (designated the FIP200-4A mutant) abolished its canonical autophagy function in vitro. Furthermore, we created a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo, providing direct support for the essential role of the ULK1/Atg13/FIP200/Atg101 complex in the process beyond previous studies relying on the complete knockout of individual components. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth. These studies provide the first genetic evidence linking an Atg's autophagy and nonautophagic functions to different biological processes in vivo. [ABSTRACT FROM AUTHOR]