Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria.
Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria.
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DOI：
10.1016/j.celrep.2016.02.030
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发表时间：
2016-03-15
期刊：
影响因子：
8.8
通讯作者：
Foskett JK
中科院分区：
文献类型：
--
作者：
Cárdenas C;Müller M;McNeal A;Lovy A;Jaňa F;Bustos G;Urra F;Smith N;Molgó J;Diehl JA;Ridky TW;Foskett JK
在缺乏低水平内质网-线粒体Ca 2+转移的情况下，ATP水平下降，并且诱导AMPK依赖性、mTOR非依赖性自噬作为许多细胞类型中的基本存活机制。在这里，我们证明了致瘤性癌细胞系、转化的原代人成纤维细胞和体内肿瘤的反应相似，但自噬不足以存活，癌细胞死亡，而正常细胞则幸免于难。癌细胞死亡是由于受损的生物能量学，其可以用代谢底物或核苷酸拯救，并且由与其增殖期间的有丝分裂灾难相关的坏死引起。我们的研究结果揭示了一个意想不到的依赖于组成性的Ca 2+转移到线粒体的致瘤细胞的活力，并建议线粒体Ca 2+成瘾是癌细胞的一个特点。
In the absence of low-level endoplasmic reticulum-to-mitochondrial Ca2+ transfer, ATP levels fall and AMPK-dependent, mTOR-independent autophagy is induced as an essential survival mechanism in many cell types. Here we demonstrate that tumorigenic cancer cell lines, transformed primary human fibroblasts and tumors in vivo respond similarly, but autophagy is insufficient for survival, and cancer cells die while their normal counterparts are spared. Cancer cell death is due to compromised bioenergetics that can be rescued with metabolic substrates or nucleotides, and caused by necrosis associated with mitotic catastrophe during their proliferation. Our findings reveal an unexpected dependency on constitutive Ca2+ transfer to mitochondria for viability of tumorigenic cells and suggest that mitochondrial Ca2+ addiction is a feature of cancer cells.