SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2
Barrie Peck,Chun-Yuan Chen,Ka-Kei Ho,Paolo Di Fruscia,Stephen S. Myatt,R. Charles Coombes,Matthew J. Fuchter,Chwan-Deng Hsiao,Eric Lam +8 more
TLDR
It is suggested that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death and that p53 mediates the cytotoxic function of Sirtinol and Salermide.Abstract:
SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 μmol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G1 at comparable concentrations. In vitro SIRTassays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermideinduced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844–55. ©2010 AACR.read more
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Forkhead box proteins: tuning forks for transcriptional harmony
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SIRT2 Maintains Genome Integrity and Suppresses Tumorigenesis through Regulating APC/C Activity
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Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome.
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TL;DR: The acetylase inhibitor spermidine and the sirtuin-1 activator resveratrol disrupt the antagonistic network of acetylases and deacetylases that regulate autophagy.
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Sirtuin activators and inhibitors.
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