Mohan John, Gandhi Alankaram Arul, Bhavya Balan Chandrika, Rashmi Ramachandran, Karunagaran Devarajan, Indu Ramachandran, Santhoshkumar Thankayyan Ratnabhai
Department of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Poojappura, Trivandrum-695 014, Kerala, India.
J Biol Chem. 2006 Jun 30;281(26):17599-611. doi: 10.1074/jbc.M602641200. Epub 2006 Apr 14.
Polyphenol phytoalexin (resveratrol), found in grapes and red wine is a strong chemopreventive agent with promising safety records with human consumption and unique forms of cell death induction in a variety of tumor cells. However, the mechanism of resveratrol-induced apoptosis upstream of mitochondria is still not defined. The results from this study suggest that caspase-2 activation occurs upstream of mitochondria in resveratrol-treated cells. The upstream activation of caspase-2 is not dependent on its antioxidant property or NF-kappaB inhibition. The activated caspase-2 triggers mitochondrial apoptotic events by inducing conformational changes in Bax/Bak with subsequent release of cytochrome c, apoptosis-inducing factor, and endonuclease G. Caspase-8 activation seems to be independent of these events and does not appear to be mediated by classical death receptor processing or downstream caspases. Both caspase-2 and caspase-8 contribute toward the mitochondrial translocation of Bid, since neither caspase-8 inhibition nor caspase-2 inhibition could prevent translocation of Bid DsRed into mitochondria. Caspase-2 inhibitors or antisense silencing of caspase-2 prevented cell death induced by resveratrol and partially prevented processing of downstream caspases, including caspase-9, caspase-3, and caspase-8. Studies using mouse embryonic fibroblasts deficient for both Bax and Bak indicate the contribution of both Bax and Bak in mediating cell death induced by resveratrol and the existence of Bax/Bak-independent cell death possibly through caspase-8- or caspase-2-mediated mitochondria-independent downstream caspase processing.
在葡萄和红酒中发现的多酚植物抗毒素（白藜芦醇）是一种强大的化学预防剂，在人类食用方面具有良好的安全记录，并且能在多种肿瘤细胞中诱导独特形式的细胞死亡。然而，白藜芦醇诱导的线粒体上游凋亡机制仍未明确。本研究结果表明，在白藜芦醇处理的细胞中，caspase-2的激活发生在线粒体上游。caspase-2的上游激活不依赖于其抗氧化特性或对NF-κB的抑制作用。激活的caspase-2通过诱导Bax/Bak的构象变化，随后释放细胞色素c、凋亡诱导因子和核酸内切酶G，触发线粒体凋亡事件。caspase-8的激活似乎独立于这些事件，并且似乎不是由经典的死亡受体加工或下游caspase介导的。caspase-2和caspase-8都有助于Bid的线粒体转位，因为caspase-8抑制或caspase-2抑制都不能阻止Bid DsRed转位到线粒体中。caspase-2抑制剂或caspase-2的反义沉默可阻止白藜芦醇诱导的细胞死亡，并部分阻止下游caspase的加工，包括caspase-9、caspase-3和caspase-8。使用同时缺乏Bax和Bak的小鼠胚胎成纤维细胞进行的研究表明，Bax和Bak在介导白藜芦醇诱导的细胞死亡中都有作用，并且可能通过caspase-8或caspase-2介导的不依赖线粒体的下游caspase加工存在不依赖Bax/Bak的细胞死亡。
