Upregulation of CASP9 through NF-κB and Its Target MiR-1276 Contributed to TNFα-promoted Apoptosis of Cancer Cells Induced by Doxorubicin.

：Under some conditions, nuclear factor-κB (NF-κB) has a pro-apoptotic role, but the mechanisms underlying this function remain unclear. This study demonstrated that NF-κB directly binds to CASP9 and miR1276 in tumor necrosis factor α (TNFα)-treated HeLa and HepG2 cells. NF-κB upregulated CASP9 expression, whereas downregulated miR1276 expression in the TNFα-treated cells. The miR1276 repressed CASP9 expression in both cells. As a result, a typical NF-κB-mediated coherent feed-forward loop was formed in the TNFα-treated cells. It was proposed that the NF-κB-mediated loop may contribute to cell apoptosis under certain conditions. This opinion was supported by the following evidence: TNFα promoted the apoptosis of HeLa and HepG2 cells induced by doxorubicin (DOX). CASP9 was significantly upregulated and activated by TNFα in the DOX-induced cells. Moreover, a known inhibitor of CASP9 activation significantly repressed the TNFα promotion of apoptosis induced by DOX. These findings indicate that CASP9 is a new mediator of the NF-κB pro-apoptotic pathway, at least in such conditions. This study therefore provides new insights into the pro-apoptotic role of NF-κB. The results also shed new light on the molecular mechanism underlying TNFα-promotion of cancer cells apoptosis induced by some anticancer drugs such as DOX.

Citation

Fei Zhou, Yun Li, Yisheng Huang, Jian Wu, Qinhan Wu, Hui Zhu, Jinke Wang. Upregulation of CASP9 through NF-κB and Its Target MiR-1276 Contributed to TNFα-promoted Apoptosis of Cancer Cells Induced by Doxorubicin. International journal of molecular sciences. 2020 Mar 26;21(7)

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PMID: 32225068

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