SirT1 Is an Inhibitor of Proliferation and Tumor Formation in Colon Cancer
SirT1 Is an Inhibitor of Proliferation and Tumor Formation in Colon Cancer
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SirT1 是结肠癌增殖和肿瘤形成的抑制剂
DOI：
10.1074/jbc.m109.000034
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发表时间：
2009-07-03
影响因子：
4.8
通讯作者：
Chen, Jiandong
中科院分区：
文献类型：
--
作者：
Kabra, Neha;Li, Zhenyu;Chen, Jiandong
NAD依赖性去乙酰化酶SirT 1调节参与应激反应和细胞存活的因子，并且是激活剂和抑制剂的潜在药物靶标。确定SirT 1在肿瘤细胞中的功能对于其在癌症治疗中的靶向是重要的。我们发现，通过短发夹RNA敲低SirT 1可加速HCT 116细胞的肿瘤异种移植物形成，而SirT 1过表达可抑制肿瘤形成。此外，药理学抑制SirT 1刺激生长因子剥夺条件下的细胞增殖。特别地，SirT 1抑制也使细胞对化疗药物引起的细胞凋亡敏感。免疫组化染色显示SirT 1在正常结肠黏膜和良性腺瘤中呈高表达。SirT 1过表达在I/II/III期结直肠腺癌中的比例为25%，但在晚期IV期肿瘤中很少发现。此外，类似于30%的癌显示低于正常的SirT 1表达。这种模式与SirT 1在癌症发展过程中具有多效性作用（抗增殖和抗凋亡）一致。这些结果表明了使用SirT 1激活剂和抑制剂预防和治疗结肠癌的基本原理。
The NAD-dependent deacetylase SirT1 regulates factors involved in stress response and cell survival and is a potential drug target of activators and inhibitors. Determination of SirT1 function in tumor cells is important for its targeting in cancer therapy. We found that SirT1 knockdown by short hairpin RNA accelerates tumor xenograft formation by HCT116 cells, whereas SirT1 overexpression inhibits tumor formation. Furthermore, pharmacological inhibition of SirT1 stimulates cell proliferation under conditions of growth factor deprivation. Paradoxically, SirT1 inhibition also sensitizes cells to apoptosis by chemotherapy drugs. Immunohistochemical staining revealed high level SirT1 in normal colon mucosa and benign adenomas. SirT1 overexpression was observed in similar to 25% of stage I/II/III colorectal adenocarcinomas but rarely found in advanced stage IV tumors. Furthermore, similar to 30% of carcinomas showed lower than normal SirT1 expression. This pattern is consistent with SirT1 having pleiotropic effects during cancer development (anti-proliferation and anti-apoptotic). These results suggest a rationale for the use of SirT1 activators and inhibitors in the prevention and treatment of colon cancer.