Identification of Sirtuin 3, a mitochondrial protein deacetylase, as a new contributor to tamoxifen resistance in breast cancer cells.

Abstract

The current study reports a previously unappreciated role of Sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, in altering sensitivity of breast cancer cells to tamoxifen (Tam), a commonly used anti-estrogen agent. We showed that SIRT3 was significantly up-regulated at both mRNA and protein levels in the Tam-resistance human breast cancer cell line MTR-3, which was derived from MCF-7 line by continuous selective culture in the presence of 1μM of Tam for two years. We further demonstrated that SIRT3 was rapidly up-regulated in the sensitive MCF-7 cells following exposure to Tam. Transfection of MCF-7 cells with a SIRT3 expression plasmid decreased cellular sensitivity to Tam and blocked the Tam-induced apoptosis. Furthermore, silencing of SIRT3 expression in MTR-3 cells sensitized the resistant cells to Tam and enhanced apoptotic cell death. MTR-3 cells with silencing of SIRT3 expression showed increases in the mitochondrial content of ERβ, ROS level and apoptosis. These results not only uncovered a new role for SIRT3 in cancer but also identified this mitochondrial protein deacetylase as a previously unrecognized factor that participates in regulation of Tam sensitivity in breast cancer cells. Thus, SIRT3 might be considered as a potential target for overcoming Tam resistance in treatment of breast cancer.

• Authors: Li Zhang, Xingcong Ren, Yan Cheng, Kathryn Huber-Keener, Xiuping Liu, Yi Zhang, Yun-Sheng Yuan, Jay W Yang, Chang-Gong Liu, Jin-Ming Yang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 86 Issue 6 Pg. 726-33 (Sep 15 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23856293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Hormonal
• Estrogen Receptor beta
• RNA, Small Interfering
• Reactive Oxygen Species
• Tamoxifen
• SIRT3 protein, human
• Sirtuin 3

Topics

• Antineoplastic Agents, Hormonal (pharmacology)
• Apoptosis (genetics)
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Estrogen Receptor beta (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mitochondria (drug effects, enzymology, genetics)
• RNA, Small Interfering (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Sirtuin 3 (antagonists & inhibitors, genetics, metabolism)
• Tamoxifen (pharmacology)