Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis
Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis
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DOI：
10.1101/gad.2016311
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发表时间：
2011-03-01
影响因子：
10.5
通讯作者：
White, Eileen
中科院分区：
文献类型：
--
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
自噬是细胞在饥饿时支持代谢和在应激时清除受损蛋白质和细胞器的一种分解代谢途径。我们在这里报告的H-ras（V12）或K-ras（V12）癌基因的表达上调基础自噬，这是需要在饥饿和肿瘤发生的肿瘤细胞生存。在表达Ras的细胞中，有缺陷的自噬体形成或货物递送导致异常线粒体的积累和氧消耗减少。自噬缺陷还导致三羧酸（TCA）循环代谢产物和饥饿时的能量消耗。由于线粒体在饥饿中维持Ras表达细胞的活力，因此需要自噬来维持支持Ras驱动的肿瘤生长所必需的功能性线粒体库。携带Ras激活突变的人类癌细胞系通常具有高水平的基础自噬，并且在这些细胞系的子集中，下调必需自噬蛋白的表达损害细胞生长。由于Ras突变的癌症预后不良，这种“自噬成瘾”表明，靶向自噬和线粒体代谢是治疗这些侵袭性癌症的有价值的新方法。
Autophagy is a catabolic pathway used by cells to support metabolism in response to starvation and to clear damaged proteins and organelles in response to stress. We report here that expression of a H-ras(V12) or K-ras(V12) oncogene up-regulates basal autophagy, which is required for tumor cell survival in starvation and in tumorigenesis. In Ras-expressing cells, defective autophagosome formation or cargo delivery causes accumulation of abnormal mitochondria and reduced oxygen consumption. Autophagy defects also lead to tricarboxylic acid (TCA) cycle metabolite and energy depletion in starvation. As mitochondria sustain viability of Ras-expressing cells in starvation, autophagy is required to maintain the pool of functional mitochondria necessary to support growth of Ras-driven tumors. Human cancer cell lines bearing activating mutations in Ras commonly have high levels of basal autophagy, and, in a subset of these, down-regulating the expression of essential autophagy proteins impaired cell growth. As cancers with Ras mutations have a poor prognosis, this "autophagy addiction'' suggests that targeting autophagy and mitochondrial metabolism are valuable new approaches to treat these aggressive cancers.