Requirement for ERK activation in cisplatin-induced apoptosis
Requirement for ERK activation in cisplatin-induced apoptosis
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DOI：
10.1074/jbc.m004583200
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发表时间：
2000-12-15
影响因子：
4.8
通讯作者：
Holbrook, NJ
中科院分区：
文献类型：
--
作者：
Wang, XT;Martindale, JL;Holbrook, NJ
顺铂激活多种信号转导途径，参与协调细胞对应激的反应。在这里，我们证明了细胞外信号调节蛋白激酶（ERK）的需要，ERK是丝裂原激活蛋白激酶家族的成员，介导顺铂诱导的人宫颈癌HeLa细胞凋亡。顺铂治疗导致 ERK 激活呈剂量和时间依赖性。多项观察结果支持 ERK 活性升高导致细胞死亡：1) PD98059 和 U0126（MEK/ERK 信号通路的化学抑制剂）可防止细胞凋亡； 2）用ERK通路激活剂TPA预处理细胞，增强细胞对顺铂的敏感性； 3)苏拉明，一种生长因子受体拮抗剂，极大地抑制ERK激活，同样抑制顺铂诱导的细胞凋亡；最后，4) 选择顺铂抗性的 HeLa 细胞变体显示顺铂治疗后 ERK 激活减少。顺铂诱导的细胞凋亡与细胞色素 c 的释放和随后的 caspase-3 激活有关，这两种情况都可以通过 MEK 抑制剂治疗来预防。然而，Caspase 抑制剂苯甲氧羰基-Val-Ala-Asp-氟甲基酮可保护 HeLa 细胞免于凋亡，而不影响 ERK 激活。综上所述，我们的研究结果表明 ERK 激活在介导顺铂诱导的 HeLa 细胞凋亡中发挥着积极作用，并且在 caspase 激活的上游发挥作用以启动凋亡信号。
Cisplatin activates multiple signal transduction pathways involved in coordinating cellular responses to stress, Here we demonstrate a requirement for extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase family in mediating cisplatin-induced apoptosis of human cervical carcinoma HeLa cells. Cisplatin treatment resulted in dose- and time- dependent activation of ERK, That elevated ERK activity contributed to cell death by cisplatin was supported by several observations: 1) PD98059 and U0126, chemical inhibitors of the MEK/ERK signaling pathway, prevented apoptosis; 2) pretreatment of cells with TPA, an activator of the ERK pathway, enhanced their sensitivity to cisplatin; 3) suramin, a growth factor receptor antagonist that greatly suppressed ERK activation, likewise inhibited cisplatin-induced apoptosis; and, finally, 4) HeLa cell variants selected for cisplatin resistance showed reduced activation of ERK following cisplatin treatment. Cisplatin-induced apoptosis was associated with cytochrome c release and subsequent caspase-3 activation, both of which could be prevented by treatment with the MEK inhibitors. However, the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone protected HeLa cells against apoptosis without affecting ERK activation. Taken together, our findings suggest that ERK activation plays an active role in mediating cisplatin-induced apoptosis of HeLa cells and functions upstream of caspase activation to initiate the apoptotic signal.