Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells
Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells
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DOI：
10.1038/sj.onc.1209049
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Kaneki, M
中科院分区：
文献类型：
--
作者：
Ota, H;Tokunaga, E;Kaneki, M
诱导衰老样生长阻滞已被认为是化疗药物抗癌作用的一个假定因素。临床试验正在评估I类和II类组蛋白去乙酰化酶抑制剂治疗恶性肿瘤的疗效。然而，Sirt1是一种依赖NAD（+）的去乙酰化酶，属于III类组蛋白去乙酰化酶，抑制剂的潜在抗增殖作用尚未被探索。在这里，我们发现Sirt1抑制剂Sirtinol在人乳腺癌MCF-7细胞和肺癌H1299细胞中诱导衰老样生长停滞，其特征是诱导衰老相关的β -半乳糖苷酶活性和增加纤溶酶原激活物抑制剂1的表达。sirtinol诱导的衰老样生长停滞伴随着丝裂原活化蛋白激酶（MAPK）途径的激活受损，即细胞外调节蛋白激酶、c-jun n-末端激酶和p38 MAPK，以响应表皮生长因子（EGF）和胰岛素样生长因子-i （IGF-I）。与未处理的细胞相比，sirtinol处理的衰老细胞中活性Ras减少。然而，经Sirtinol处理后，EGF和IGF-I受体的酪氨酸磷酸化和Akt/PKB活化未发生改变。这些结果表明Sirt1抑制剂可能具有抗癌潜力，Ras-MAPK通路的激活受损可能参与了Sirtinol诱导的衰老样生长停滞程序。
The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase ( MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.