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

Li Zhang, Xingcong Ren, Yan Cheng, Kathryn Huber-Keener, Xiuping Liu, Yi Zhang, Yun S. Yuan, Jay W. Yang, Chang G. Liu, Jin M. Yang

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 antiestrogen 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 1 μM 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 Taminduced 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.

Original languageEnglish
Pages (from-to)726-733
Number of pages8
JournalBiochemical Pharmacology
Volume86
Issue number6
DOIs
StatePublished - 2013

Bibliographical note

Funding Information:
This study was supported by grants from Elsa Pardee Foundation and the Department of Defense BC103654 , and from National Natural Sciences Foundation of China ( 81072146 ; 81101913 ) and Natural Science Foundation of Jiangsu Province of China ( BK2010224 ). We thank Dr. Planas-Silva for providing us with the tamoxifen-resistant breast cancer cell line. We thank Dr. Kent Vrana for his helpful comments on this manuscript.

Keywords

  • Breast cancer
  • Drug resistance
  • ERb
  • SIRT3
  • Tamoxifen

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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