Activation of AMP-Activated Protein Kinase is Involved in Vincristine-Induced Cell Apoptosis in B16 Melanoma Cell
Activation of AMP-Activated Protein Kinase is Involved in Vincristine-Induced Cell Apoptosis in B16 Melanoma Cell
复制标题
DOI：
10.1002/jcp.22522
复制
发表时间：
2011-07-01
影响因子：
5.6
通讯作者：
Lu, Pei-Hua
中科院分区：
文献类型：
--
作者：
Chen, Min-Bin;Shen, Wen-Xiang;Lu, Pei-Hua
长春新碱诱导黑色素瘤细胞凋亡的分子基础仍然未知。在这里，我们测试了AMP激活蛋白激酶（AMPK）在这一过程中的潜在参与。我们首次发现长春新碱在体外培养的黑色素瘤细胞中诱导AMPK激活（AMPK α，Thr 172）和乙酰辅酶A羧化酶（ACC，Ser 79）（AMPK的下游分子靶点）磷酸化。活性氧（ROS）依赖性LKB 1活化充当AMPK活化的上游信号。AMPK抑制剂（化合物C）或AMPKa siRNA敲低抑制长春新碱诱导的B16黑色素瘤细胞凋亡，而AMPK激活剂5-氨基咪唑-4-甲酰胺-1-β-核苷（AICAR）增强其作用。AMPK激活参与长春新碱诱导的p53磷酸化和稳定化，后者已知介导黑色素瘤细胞凋亡。此外，通过长春新碱激活AMPK抑制B16黑素瘤细胞中的mTOR复合物1（mTORC 1），这是诱导黑素瘤细胞凋亡的另一个重要机制。我们的研究为了解长春新碱诱导癌细胞死亡/凋亡的细胞和分子机制提供了新的见解。我们认为AMPK激活剂AICAR与长春新碱联合应用可能成为一种新的抗黑色素瘤的治疗手段。J.细胞。226：1915 - 1925，2011。(C)2010 Wiley-Liss，Inc.
The molecular basis for induction of apoptosis in melanoma cells by vincristine remains unknown. Here we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found for the first time that vincristine induces AMPK activation (AMPK alpha, Thr 172) and Acetyl-CoA carboxylase (ACC, Ser 79) (a downstream molecular target of AMPK) phosphorylation in cultured melanoma cells in vitro. Reactive oxygen species (ROS) dependent LKB1 activation serves as the upstream signal for AMPK activation. AMPK inhibitor (compound C) or AMPKa siRNA knockdown inhibits vincristine induced B16 melanoma cell apoptosis, while AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-riboside (AICAR) enhances it. AMPK activation is involved in vincristine induced p53 phosphorylation and stabilization, the latter is known to mediate melanoma cell apoptosis. Further, activation of AMPK by vincristine inhibits mTOR Complex 1 (mTORC1) in B16 melanoma cells, which serves as another important mechanism to induce melanoma cell apoptosis. Our study provides new insights into understanding the cellular and molecular mechanisms of vincristine induced cancer cell death/apoptosis. We suggest that combining AMPK activator AICAR with vincristine may have potential to be used as a new therapeutic intervention against melanoma. J. Cell. Physiol. 226: 1915-1925, 2011. (C) 2010 Wiley-Liss, Inc.