SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2
SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2
复制标题
DOI：
10.1158/1535-7163.mct-09-0971
复制
发表时间：
2010-04-01
影响因子：
5.7
通讯作者：
Lam, Eric W. -F.
中科院分区：
文献类型：
--
作者：
Peck, Barrie;Chen, Chun-Yuan;Lam, Eric W. -F.
SIRT蛋白在肿瘤细胞的生存和耐药过程中发挥着重要作用，尤其是在化疗过程中。在这项研究中，我们研究了三种SIRT抑制剂Sirtinol、Salermide和EX527的效力、特异性和细胞靶点。细胞增殖和细胞周期分析表明，Sirtinol和Salermide在50 μ mol/L或以上浓度时能有效诱导MCF-7细胞死亡，而EX527则不能。相反，在相同浓度下，EX527在G(1)时引起细胞周期阻滞。使用p53肽底物的体外SIRT实验表明，这三种化合物都是有效的SIRT1/2抑制剂，其中EX527对SIRT1具有最高的抑制活性。计算对接分析表明Sirtinol和Salermide对SIRT1/2具有高度的选择性，而EX527对SIRT1具有高特异性，而对SIRT2没有特异性。一致地，Sirtinol和Salermide，而不是EX527，导致MCF-7细胞中SIRT1/2靶点p53和SIRT2靶点微管蛋白在体内乙酰化，这表明EX527对SIRT2的抑制无效，p53介导Sirtinol和Salermide的细胞毒性功能。对乳腺癌细胞系和p53缺陷小鼠成纤维细胞的研究证实，p53对于Sirtinol和saleramide诱导的细胞凋亡至关重要。此外，我们发现使用小干扰RNA沉默两个sirt，而不是单独沉默SIRT1和SIRT2，可以诱导MCF-7细胞死亡。总之，我们的研究结果确定了这些新型抑制剂的特异性和细胞靶点，并表明SIRT抑制剂需要联合靶向SIRT1和SIRT2来诱导p53乙酰化和细胞死亡。巨蟹座；9 (4);844 - 55。(c) 2010年aacr。
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 mu mol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G(1) at comparable concentrations. In vitro SIRT assays 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 Salermide-induced 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. (C) 2010 AACR.