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ABT737 enhances ovarian cancer cells sensitivity to cisplatin through regulation of mitochondrial fission via Sirt3 activation

Hou, Lin, Wang, Ruobing, Wei, Haifeng, Li, Shouqing, Liu, Lei, Lu, Xiaodan, Yu, Huimei, Liu, Ziling
Life sciences 2019 v.232 pp. 116561
Western blotting, apoptosis, cisplatin, drug therapy, flow cytometry, fluorescent antibody technique, fluorometry, histone deacetylase, membrane potential, mitochondria, mitochondrial membrane, neoplasm cells, ovarian neoplasms, prognosis, staining
The poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells.Apoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis.Cisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process.This study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.