Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation
Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation
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DOI：
10.1074/jbc.m110.202440
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发表时间：
2011-08-19
影响因子：
4.8
通讯作者：
Chandra, Dhyan
中科院分区：
文献类型：
--
作者：
Gogada, Raghu;Prabhu, Varun;Chandra, Dhyan
白藜芦醇是一种天然存在的植物抗毒素，已知可诱导多种癌细胞类型的凋亡，但其潜在的分子机制仍不清楚。在这里，我们表明，白藜芦醇诱导p53非依赖性，X-连锁的凋亡抑制蛋白（XIAP）介导的Bax易位到线粒体，在那里它进行寡聚化，启动凋亡。白藜芦醇处理促进Bax和XIAP之间的相互作用在细胞质和线粒体上，表明XIAP在Bax的激活和易位到线粒体中起着关键作用。这个过程不涉及p53，但需要积累的Bim和t-Bid的线粒体。Bax主要在线粒体上进行同源寡聚化，并在细胞色素c向胞质溶胶的释放中发挥主要作用。巴克是调节线粒体膜透化的另一个关键蛋白，它不与p53相互作用，但继续与Bcl-xL结合。因此，在白藜芦醇诱导的细胞凋亡过程中，巴克的促凋亡功能仍然受到抑制。半胱天冬酶-9沉默抑制白藜芦醇诱导的半胱天冬酶激活，而半胱天冬酶-8敲低不影响半胱天冬酶活性，表明白藜芦醇诱导半胱天冬酶-9依赖性细胞凋亡。总之，我们的研究结果表征了白藜芦醇诱导的caspase激活和随后的癌细胞凋亡的分子机制。
Resveratrol, a naturally occurring phytoalexin, is known to induce apoptosis in multiple cancer cell types, but the underlying molecular mechanisms remain unclear. Here, we show that resveratrol induced p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated translocation of Bax to mitochondria where it underwent oligomerization to initiate apoptosis. Resveratrol treatment promoted interaction between Bax and XIAP in the cytosol and on mitochondria, suggesting that XIAP plays a critical role in the activation and translocation of Bax to mitochondria. This process did not involve p53 but required accumulation of Bim and t-Bid on mitochondria. Bax primarily underwent homo-oligomerization on mitochondria and played a major role in release of cytochrome c to the cytosol. Bak, another key protein that regulates the mitochondrial membrane permeabilization, did not interact with p53 but continued to associate with Bcl-xL. Thus, the proapoptotic function of Bak remained suppressed during resveratrol-induced apoptosis. Caspase-9 silencing inhibited resveratrol-induced caspase activation, whereas caspase-8 knockdown did not affect caspase activity, suggesting that resveratrol induces caspase-9-dependent apoptosis. Together, our findings characterize the molecular mechanisms of resveratrol-induced caspase activation and subsequent apoptosis in cancer cells.