Abstract B109: The role of SIRT6 in drug resistance and cellular senescence in cancer.

Abstract

Abstract Introduction: The Sirtuin family consists of 7 members. They comprize highly conserved NAD+-dependent deacetylases that play an important role in a board spectrum of cellular processes, including metabolism, differentiation, survival and cellular senescence. It has also been suggested that these proteins are central to cancer development and drug resistance. Recent studies have documented that SIRT6, a nuclear chromatin-associated protein, has a key role in genomic stability and degenerative pathologies associated with ageing. Moreover, SIRT6 has been reported to have a function in the regulation of DNA damage repair. Therefore, this research aims to investigate the role of SIRT6 in drug resistance and cellular senescence in cancer cells. Methods: Cell lines that we have used in this research consist of sensitive and resistant breast cancer cells, Hela cells and mouse embryonic fibroblasts (MEFs). To investigate the role of SIRT6 in drug resistance, we treated cells with either epirubicin or paclitaxel, then performed immunofluorescent, comet and repair assays to investigate DNA damage repair. Clonogenic and beta-galactosidase assays were also used to investigate long-term survival and cellular senescence. Results: We found that SIRT6 is elevated in drug resistant cells compared to drug sensitive parental cells and that SIRT6 mediates drug resistance by increasing DNA damage repair. Sirt6-/- MEFs have lower levels of γH2AX accumulation compared to WT MEFs. These higher levels of SIRT6 are also associated with the lower activities of p53 and FOXO3a which are two important cell cycle/survival regulators. Here, we show that depletion of SIRT6 in cancer cells results in a decrease in long-term survival and lower HR and NHEJ DNA repair activity. SIRT6-deficeint cells also exhibit the induction of senescence-associated β-galactosidase activity and flat cell morphology. Conclusion: Our results suggest a novel role of SIRT6 in epirubicin and paclitaxel treatment resistance and cellular senescence. SIRT6 could be a potential biomarker for identifying tumors that are likely to be resistant to these chemotherapeutic agents. It might be also a useful therapeutic target for the prevention of acquired drug resistance and for improving the efficiency of drug treatment. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B109. Citation Format: Mattaka Khongkow, Eric Lam. The role of SIRT6 in drug resistance and cellular senescence in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B109.