Regulation of tumor cell mitochondrial Homeostasis by an organelle-specific Hsp90 chaperone network
Regulation of tumor cell mitochondrial Homeostasis by an organelle-specific Hsp90 chaperone network
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DOI：
10.1016/j.cell.2007.08.028
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发表时间：
2007-10-19
期刊：
影响因子：
64.5
通讯作者：
Altieri, Dario C.
中科院分区：
文献类型：
--
作者：
Kang, Byoung Heon;Plescia, Janet;Altieri, Dario C.
分子伴侣，特别是热休克蛋白90(Hsp90)家族的成员，被认为可以促进肿瘤细胞的存活，但这一功能尚不清楚。在这里，我们表明，肿瘤细胞的线粒体，但不是大多数正常组织，含有Hsp90及其相关分子TRAP-1。这些伴侣与亲环素D相互作用，亲环素D是一种免疫亲和素，可诱导线粒体细胞死亡，并通过蛋白质折叠/重折叠机制拮抗其功能。使用针对线粒体的新型Hsp90 ATPase拮抗剂来禁用这一途径会导致线粒体功能的突然崩溃和选择性的肿瘤细胞死亡。因此，Hsp90导向的伴侣蛋白是线粒体完整性的调节者，它们的细胞器特异性拮抗剂可能提供一类以前未描述的有效抗癌药物。
Molecular chaperones, especially members of the heat shock protein 90 ( Hsp90) family, are thought to promote tumor cell survival, but this function is not well understood. Here, we show that mitochondria of tumor cells, but not most normal tissues, contain Hsp90 and its related molecule, TRAP-1. These chaperones interact with Cyclophilin D, an immunophilin that induces mitochondrial cell death, and antagonize its function via protein folding/refolding mechanisms. Disabling this pathway using novel Hsp90 ATPase antagonists directed to mitochondria causes sudden collapse of mitochondrial function and selective tumor cell death. Therefore, Hsp90 directed chaperones are regulators of mitochondrial integrity, and their organelle-specific antagonists may provide a previously undescribed class of potent anticancer agents.