Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt.
Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt.
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DOI：
10.1038/sj.bjc.6604223
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发表时间：
2008-02-26
影响因子：
8.8
通讯作者：
Tsang, B. K.
中科院分区：
文献类型：
--
作者：
Yang, X.;Fraser, M.;Abedini, M. R.;Bai, T.;Tsang, B. K.
顺铂是卵巢癌的一线化疗药物，尽管化疗耐药限制了治疗的成功。细胞凋亡是顺铂敏感性的重要决定因素，通过caspase依赖性和非依赖性机制发生。Akt蛋白激酶的激活，通常在卵巢肿瘤中观察到，通过抑制caspase依赖性凋亡，赋予卵巢癌细胞抗性。然而，Akt对顺铂诱导的不依赖caspase的细胞凋亡的影响尚不清楚。我们发现，在化疗敏感的卵巢癌细胞中，顺铂诱导凋亡诱导因子（AIF）的线粒体释放和核易位，AIF是caspase不依赖的细胞凋亡和AIF依赖的细胞凋亡的介质。顺铂不能在化疗耐药变异细胞中诱导这些作用。AIF致敏耐药细胞对顺铂诱导的凋亡的过度表达。最后，Akt的激活减弱了顺铂诱导的线粒体释放、AIF的核积累和化疗敏感细胞的凋亡，而抑制Akt的活性促进了这些作用，并使化疗耐药细胞对AIF依赖、顺铂诱导的凋亡敏感。这些结果表明，顺铂诱导的细胞凋亡在一定程度上是通过涉及AIF的caspase不依赖机制进行的，Akt的激活通过阻断该途径赋予顺铂诱导的细胞凋亡抗性。这些结果为化疗耐药的分子机制提供了新的见解，并表明抑制Akt活性可能是治疗顺铂耐药卵巢癌的一种新的治疗方法。
Cisplatin is a first-line chemotherapeutic for ovarian cancer, although chemoresistance limits treatment success. Apoptosis, an important determinant of cisplatin sensitivity, occurs via caspase-dependent and -independent mechanisms. Activation of the protein kinase Akt, commonly observed in ovarian tumours, confers resistance to ovarian cancer cells via inhibition of caspase-dependent apoptosis. However, the effect of Akt on cisplatin-induced, caspase-independent apoptosis remains unclear. We show that in chemosensitive ovarian cancer cells, cisplatin induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor (AIF), a mediator of caspase-independent apoptosis, and AIF-dependent apoptosis. Cisplatin failed to induce these effects in the chemoresistant variant cells. Overexpression of AIF sensitised resistant cells to cisplatin-induced apoptosis. Finally, activation of Akt attenuated the cisplatin-induced mitochondrial release and nuclear accumulation of AIF and apoptosis in chemosensitive cells, whereas inhibition of Akt activity facilitated these effects and sensitised chemoresistant cells to AIF-dependent, cisplatin-induced apoptosis. These results suggest that cisplatin-induced apoptosis proceeds, in part, via a caspase-independent mechanism involving AIF, and that Akt activation confers resistance to cisplatin-induced apoptosis by blocking this pathway. These results provide insights into the molecular mechanism of chemoresistance, and suggest that inhibition of Akt activity may represent a novel therapeutic approach to the treatment of cisplatin-resistant ovarian cancer.
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