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Induction of Stress Induced Premature Senescence by Sirtuin-7 Inhibition: A Novel Mechanism for Multi Drug Resistance

Abstract

Ahmad Aljada, Ayman Saleh and Shaker A Mousa

Stress-Induced Premature Senescence (SIPS), a senescence-like state achieved as a result of a variety of stresses, is associated with relative inability to undergo apoptosis. Sirtuins are a family of histone deacetylases known primarily for their implication in the aging process; however their role in cancer, an aging associated disease, is still poorly understood. In the present study, we investigated whether alterations in sirtuins expression may be associated with aggressive tumor behavior. We have compared expression profiles of sirtuins between drug sensitive and resistant cancer cells MCF7, SaOS-2, A2780 and HL-60. Expression levels of Sirtuin 1-6 varied among cell lines; however Sirtuin-7 was significantly reduced in all chemoresistant cells tested. Knockdown of Sirt7 expression in human breast MCF7 cell line by RNAi induced senescence-associated β-galactosidase activity, reduced cell proliferation rate, induced drug resistance and increased cell migration, suggesting that this gene may play an active role in regulating cancer cell response to stress. Thus, Sirt7 may represent a compelling target for anti-cancer interventions