Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway
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Na-Na Tao1,*, Hong-Zhong Zhou1,*, Hua Tang1,2,*, Xue-Fei Cai1, Wen-Lu Zhang1, Ji-Hua Ren1, Li Zhou3, Xiang Chen1, Ke Chen1, Wan-Yu Li1, Bo Liu1, Qiu-Xia Yang1, Sheng-Tao Cheng1, Li-Xia Huang1, Ai-Long Huang1,2, Juan Chen1
1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China
3Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
*These authors have contributed equally to this work
Juan Chen, email: [email protected]
Ai-Long Huang, email: [email protected]
Keywords: hepatocellular carcinoma, SIRT3, drug sensitivity, glutathione S-transferase pi 1, c-Jun N-terminal kinase
Received: January 17, 2016 Accepted: June 16, 2016 Published: June 29, 2016
SIRT3, a class III histone deacetylase, has been implicated in various cancers as a novel therapeutic target. In hepatocellular carcinoma (HCC), we previously reported that SIRT3 induced cell apoptosis by regulating GSK-3β/Bax signaling pathway. Downregulation of SIRT3 in HCC cells facilitates tumor cell survival. In this study, we found that chemotherapeutic agents (doxorubicin, cisplatin and epirubicin) and sorafenib treatment downregulated SIRT3 mRNA and protein levels in three HCC cell lines. MTS assay found that SIRT3 overexpression sensitized liver cancer cells to chemotherapeutic agents and sorafenib in SMMC-7721, Huh-7 and PLC/PRF/5 cell lines. Moreover, SIRT3 overexpression promoted chemotherapeutic agents-induced or sorafenib-induced apoptosis as evidenced by flow cytometry, enhanced PARP cleavage and enhanced Caspase-9 cleavage in three HCC cells. In contrast, SIRT3 silencing increased drug resistance of HCC cells to chemotherapeutic agents. Mechanistic study found that SIRT3 downregulated the mRNA and protein levels of glutathione S-transferase pi 1 (GSTP1), which is a member of phase II detoxification enzymes families involved in metabolizing for chemotherapeutic agents. Moreover, SIRT3 decreased the amount of GSTP1 that was associated with JNK, which finally contributed the activation of JNK activity and activation of downstream target c-Jun and Bim. Importantly, GSTP1 overexpression or JNK inhibitor abolished SIRT3-induced apoptosis in HCC cells exposed to chemotherapeutic agents. Finally, there was a negative correlation between SIRT3 expression and GSTP1 expression in human HCC tissues. Together, our findings revealed SIRT3 could enhance the drug sensitivity of HCC cells to an array of chemotherapeutic agents. SIRT3 may serve as a potential target for improving the chemosensitivity of HCC patients.
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