Stünkel Walter, Peh Bee Keow, Tan Yong Cheng, Nayagam Vasantha M, Wang Xukun, Salto-Tellez Manuel, Ni BinHui, Entzeroth Michael, Wood Jeanette
S*BIO PTE Ltd, 1 Singapore Science Park II, Singapore, Singapore.
Biotechnol J. 2007 Nov;2(11):1360-8. doi: 10.1002/biot.200700087.
The NAD(+)-dependent protein deacetylase SIRT1 is linked to cellular survival pathways by virtue of keeping the tumor suppressor gene p53 and members of the forkhead transcription factor family deacetylated. To validate SIRT1 as a therapeutic anti-cancer target, we performed immunohistochemistry experiments to study the in vivo expression of SIRT1 in cancer specimens. We show that human SIRT1 is highly expressed in cancer cell lines as well as in tissue samples from colon carcinoma patients. Interestingly, there is a strong cytosolic component in the SIRT1 expression pattern. We further characterized SIRT1 in p53-wild-type and -mutant cell lines and show that SIRT1 mRNA-knockdown leads to a p53-independent decrease of cell proliferation and induction of apoptosis. In addition, SIRT1 expression has been found to be inducible upon DNA damage. A previously discovered small molecule SIRT1 inhibitor with nanomolar in vitro activity has been tested in cancer relevant assays. The SIRT1 inhibitory compound showed no potent anti-proliferative activity despite hitting its molecular target within tumor cells. From these studies we conclude that it may not be sufficient to block the catalytic function of SIRT1, and that its survival effects may be mainly brought about by means other then the deacetylase function. The increased cytosolic expression of SIRT1 in cancer cells could be an indicator of such novel functions.
烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖性蛋白脱乙酰酶SIRT1与细胞存活途径相关，因为它能使肿瘤抑制基因p53和叉头转录因子家族成员保持去乙酰化状态。为了验证SIRT1作为治疗性抗癌靶点的作用，我们进行了免疫组织化学实验，以研究SIRT1在癌症标本中的体内表达情况。我们发现，人SIRT1在癌细胞系以及结肠癌患者的组织样本中高表达。有趣的是，SIRT1的表达模式中有很强的胞质成分。我们进一步在p53野生型和突变型细胞系中对SIRT1进行了表征，结果表明，敲低SIRT1 mRNA会导致细胞增殖以p53非依赖的方式减少，并诱导细胞凋亡。此外，还发现DNA损伤时SIRT1的表达可被诱导。一种先前发现的具有纳摩尔体外活性的小分子SIRT1抑制剂已在癌症相关实验中进行了测试。尽管该SIRT1抑制化合物在肿瘤细胞内作用于其分子靶点，但并未显示出有效的抗增殖活性。从这些研究中我们得出结论，仅阻断SIRT1的催化功能可能并不足够，其对细胞存活的影响可能主要通过脱乙酰酶功能以外的其他方式实现。癌细胞中SIRT1胞质表达的增加可能是这些新功能的一个指标。
