Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M
Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Oncogene. 2006 Jan 12;25(2):176-85. doi: 10.1038/sj.onc.1209049.
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.
诱导类似衰老的生长停滞已被认为是化疗药物抗癌作用的一个潜在因素。目前正在进行临床试验，以评估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抑制剂（一种NAD(+)依赖性去乙酰化酶，属于III类组蛋白去乙酰化酶）的潜在抗增殖作用尚未得到探索。在此，我们表明，Sirt1抑制剂Sirtinol在人乳腺癌MCF-7细胞和肺癌H1299细胞中诱导了类似衰老的生长停滞，其特征为衰老相关β-半乳糖苷酶活性的诱导以及纤溶酶原激活物抑制剂1表达的增加。Sirtinol诱导的类似衰老的生长停滞伴随着丝裂原活化蛋白激酶（MAPK）途径（即细胞外调节蛋白激酶、c-jun N端激酶和p38 MAPK）对表皮生长因子（EGF）和胰岛素样生长因子-I（IGF-I）反应的激活受损。与未处理细胞相比，Sirtinol处理的衰老细胞中活性Ras降低。然而，Sirtinol处理并未改变EGF和IGF-I受体的酪氨酸磷酸化以及Akt/PKB的激活。这些结果表明，Sirt1抑制剂可能具有抗癌潜力，并且Ras-MAPK途径激活受损可能参与了Sirtinol诱导的类似衰老生长停滞程序。
