SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells

Xiang,Xi-Yan; Kang,Jin-Song; Yang,Xiao-Chun; Su,Jing; Wu,Yao; Yan,Xiao-Yu; Xue,Ya-Nan; Xu,Ye; Liu,Yu-He; Yu,Chun-Yan; Zhang,Zhi-Chao; Sun,Lian-Kun

doi:10.3892/ijo.2016.3552

SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells

Authors:
- Xi-Yan Xiang
- Jin-Song Kang
- Xiao-Chun Yang
- Jing Su
- Yao Wu
- Xiao-Yu Yan
- Ya-Nan Xue
- Ye Xu
- Yu-He Liu
- Chun-Yan Yu
- Zhi-Chao Zhang
- Lian-Kun Sun
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Affiliations: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China, Centre of Nephrology and Urology, Shenzhen University Health Science Centre, Shenzhen, Guangdong 518060, P.R. China, Medical Research Laboratory, Jilin Medical College, Jilin City, Jilin 132013, P.R. China, Department of Pathology, Basic Medical College, BeiHua University, Jilin City, Jilin 132013, P.R. China, State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116012, P.R. China
Published online on: June 1, 2016 https://doi.org/10.3892/ijo.2016.3552
Pages: 773-784

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Abstract

The Bcl-2 antiapoptotic proteins are important cancer therapy targets; however, their role in cancer cell metabolism remains unclear. We found that the BH3-only protein mimetic S1, a novel pan Bcl-2 inhibitor, simultaneously interrupted glucose metabolism and induced apoptosis in human SKOV3 ovarian cancer cells, which was related to the activation of SIRT3, a stress-responsive deacetylase. S1 interrupted the cellular glucose metabolism mainly through causing damage to mitochondrial respiration and inhibiting glycolysis. Moreover, S1 upregulated the gene and protein expression of SIRT3, and induced the translocation of SIRT3 from the nucleus to mitochondria. SIRT3 silencing reversed the effects of S1 on glucose metabolism and apoptosis through increasing the level of HK-II localized to the mitochondria, while a combination of the glycolysis inhibitor 2-DG and S1 intensified the cytotoxicity through further upregulation of SIRT3 expression. This study underscores an essential role of SIRT3 in the antitumor effect of Bcl-2 inhibitors in human ovarian cancer through regulating both metabolism and apoptosis. The manipulation of Bcl-2 inhibitors combined with the use of classic glycolysis inhibitors may be rational strategies to improve ovarian cancer therapy.

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