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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]

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]

Abnormal cell proliferation is a main driver of tumor formation and development, which involves the deletion, mutation, and downregulation of tumor suppressor genes. One study recently demonstrated that miR-200a plays an oncogenic role by inhibiting phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression. In the human endometrial adenocarcinoma cell line HEC-1B, suppression of miR-200a expression inhibited cell proliferation and promoted apoptosis, whereas its over-expression had no effect on proliferation and apoptosis. Furthermore, inhibition or over-expression of miR-200a increased or reduced the expression of PTEN, respectively, with no change in PTEN mRNA levels. These effects were achieved by directly targeting miR-200a to the 3′ untranslated region of the PTEN mRNA to inhibit its translation. Taken together, we propose that in HEC-1B cells, miR-200a functions as an oncogene, affecting proliferation and apoptosis by regulating the expression of the tumor suppressor PTEN at the translational level. [ABSTRACT FROM AUTHOR]

As a highly conserved nuclear protein, death domain-associated protein (Daxx) plays an important role in transcriptional control, carcinogenesis, and resistance to virus infection and so on. In order to further investigate the mechanism of Daxx, the yeast two-hybrid technique was used to screen the intra-cellular proteins interacting with Daxx. And 13 positive colonies and three proteins interacting with Daxx were obtained. One of the candidate proteins was identified as ferritin, heavy polypeptide 1(FTH1). The interaction between Daxx and FTH1 was further supported by GST pull-down and co-immunoprecipitation respectively. Then Daxx was determined to induce apoptosis and FTH1 can inhibit Daxx-mediated apoptosis. Besides, it is found that Daxx mediated apoptosis through the Fas-Daxx-ASK1-JNK1 signaling pathway, while FTH1 can inhibit the activation of JNK signaling pathway. We present evidence to demonstrate the FTH1 and Daxx are able to participate in apoptosis pathway through JNK signal molecule and FTH1 can inhibit this pathway. [ABSTRACT FROM AUTHOR]

Tanshinone I (Tan I), a diterpene quinone extracted from herbal medicine Salvia miltiorrhiza Bunge, has recently been reported to have antitumor effects. As the mechanism of its proapoptotic effects on human myeloid leukemia cells has not been extensively studied, we performed an in-depth evaluation of the effects of Tan I on apoptosis in human K562 and HL-60 cells. The results revealed that Tan I could inhibit the growth of leukemia cells and cause apoptosis in a time- and dose-dependent manner. Apoptosis was observed clearly by flow cytometry and Hoechst 33258 staining, as well as DNA fragmentation analysis. After treatment by Tan I for 48 h, the percentage of disruption of mitochondrial membrane potential (Δψm) was increased in a dose-dependent manner. Western blotting analysis demonstrated the cleavage of caspase-3 zymogen protein and a dose-dependent cleavage of poly-(ADP-ribose) polymerase. Tan I-induced apoptosis was accompanied by a significant decrease in survivin and an increase in Bax. Moreover, Tan I treatment remarkably downregulated the phosphorylation of both P85/PI3K and Akt in a time-dependent manner, and the PI3K/AKT-specific inhibitor (LY294002) mimicked the apoptosis-inducing effects of Tan I. We therefore conclude that the induction of apoptosis by Tan I in these leukemia cells is mainly related to the disruption of Δψm, the upregulation of Bax expression, and the activation of caspase-3. This process is highly correlated with the inactivation of PI3K/Akt/survivin signaling pathways. The results indicate that Tan I may serve as an effective adjunctive reagent in the treatment of leukemia. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a transcription factor important in fat metabolism and PPAR-γ agonists were recently demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. In the present study, two PPAR-γ agonists, 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) and a synthetic PPAR-γ agonist troglitazone (TGZ), were used to investigate activated PPAR-γ-induced apoptosis on human monocyte leukemia U937 and Mono Mac 6 cells in vitro. The results showed that both U937 and Mono Mac 6 cells demonstrated constitutive activation of COX-2 expression; treatment by 15d-PGJ2 and TGZ could induce apoptosis remarkably in human monocyte leukemia cells by disruption of mitochondrial membrane potential, activation of caspase-3, and causing cleavage of the caspase substrate poly (ADP-ribose) polymerase (PARP). Further studies revealed that treatment by both 15d-PGJ2 and TGZ remarkably downregulated COX-2 expression in these two kind of monocyte leukemia cells as measured by reverse transcriptase PCR (RT-PCR) and Western blot. Furthermore, the expression of Bcl-2 and Bcl-Xl and Mcl-1 was downregulated while Bax expression was upregulated concurrently after the cells were treated by these two agonists, and no variations were found in other Bcl-2 family members such as Bak, Bid, and Bad. Taken together, our results demonstrate for the first time that downregulation of cyclooxygenase-2 expression, disruption of mitochondrial membrane potential, activation of caspase-3, downregulation of Bcl-2, Bcl-Xl, and Mcl-1, and upregulation of Bax are involved in PPAR-γ agonists-induced apoptosis in these two human monocyte leukemia cells. [ABSTRACT FROM AUTHOR]