Hypoxic Enlarged Mitochondria Protect Cancer Cells From Apoptotic Stimuli
Hypoxic Enlarged Mitochondria Protect Cancer Cells From Apoptotic Stimuli
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DOI：
10.1002/jcp.21984
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发表时间：
2010-03-01
影响因子：
5.6
通讯作者：
Mazure, Nathalie M.
中科院分区：
文献类型：
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作者：
Chiche, Johanna;Rouleau, Matthieu;Mazure, Nathalie M.
众所周知，暴露于肿瘤的限制性氧微环境（缺氧）下的细胞对化疗产生耐药性，其机制尚不完全清楚。我们注意到，当暴露于长期缺氧（72小时）时，大量细胞系显示出对凋亡刺激，staurosporine或依托泊苷的保护。此外，这些细胞有异常扩大的线粒体，以hif -1依赖的方式诱导。增大的线粒体保留了它们的跨膜电位和ATP的产生。在这里，我们揭示了缺氧诱导的化疗耐药细胞的线粒体经历了hif -1依赖性和mitofusin-1介导的形态学变化，从管状网络到扩大的表型。由于线粒体融合蛋白mitofusin 1以及两个线粒体hif靶向基因BNIP3和BNIP3L的沉默，重新建立了管状形态，因此线粒体融合/裂变的不平衡发生。缺氧细胞对斯陶孢素和依泊泊苷诱导的细胞死亡不敏感，但沉默丝裂酶、BNIP3和BNIP3L可恢复敏感性。我们的研究结果表明，一些癌细胞通过诱导线粒体融合并将BNIP3和BNIP3L靶向线粒体膜，从而使这些细胞具有选择性生长优势，从而在缺氧条件下逃避细胞凋亡。j .细胞。中国生物医学工程学报，2009,31(2):448 - 457。(C) 2009 Wiley-Liss, Inc。
It is well established that cells exposed to the limiting oxygen microenvironment (hypoxia) of tumors acquire resistance to chemotherapy, through mechanisms not fully understood. We noted that a large number of cell lines showed protection from apoptotic stimuli, staurosporine, or etoposide, when exposed to long-term hypoxia (72 h). In addition, these cells had unusual enlarged mitochondria that were induced in a HIF-1-dependent manner. Enlarged mitochondria were functional as they conserved their transmembrane potential and ATP production. Here we reveal that mitochondria of hypoxia-induced chemotherapy-resistant cells undergo a HIF-1-dependent and mitofusin-1-mediated change in morphology from a tubular network to an enlarged phenotype. An imbalance in mitochondrial fusion/fission occurs since silencing of not only the mitochondrial fusion protein mitofusin 1 but also BNIP3 and BNIP3L, two mitochondrial HIF-targeted genes, reestablished a tubular morphology. Hypoxic cells were insensitive to staurosporine- and etoposide-induced cell death, but the silencing of mitofusin, BNIP3, and BNIP3L restored sensitivity. Our results demonstrate that some cancer cells have developed yet another way to evade apoptosis in hypoxia, by inducing mitochondrial fusion and targeting BNIP3 and BNIP3L to mitochondrial membranes, thereby giving these cells a selective growth advantage. J. Cell. Physiol. 222: 648-657, 2010. (C) 2009 Wiley-Liss, Inc.