SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells.
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.
Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Xi-Yan
XY
Xiang
Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Jin-Song
JS
Kang
Centre of Nephrology and Urology, Shenzhen University Health Science Centre, Shenzhen, Guangdong 518060, P.R. China.
Xiao-Chun
XC
Yang
Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Jing
J
Su
Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Yao
Y
Wu
Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Xiao-Yu
XY
Yan
Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Ya-Nan
YN
Xue
Medical Research Laboratory, Jilin Medical College, Jilin City, Jilin 132013, P.R. China.
Ye
Y
Xu
Department of Pathology, Basic Medical College, BeiHua University, Jilin City, Jilin 132013, P.R. China.
Yu-He
YH
Liu
Department of Pathology, Basic Medical College, BeiHua University, Jilin City, Jilin 132013, P.R. China.
Chun-Yan
CY
Yu
State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116012, P.R. China.
Zhi-Chao
ZC
Zhang
Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Lian-Kun
LK
Sun
D017209:Apoptosis / Q000187:drug effects; D032701:Biomimetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000235:genetics; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
C474007:Bax protein (53-86); D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D005947:Glucose