Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis
Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis
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DOI：
10.1016/j.ccr.2006.06.001
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发表时间：
2006-07-01
期刊：
影响因子：
50.3
通讯作者：
White, Eileen
中科院分区：
文献类型：
--
作者：
Degenhardt, Kurt;Mathew, Robin;White, Eileen
缺陷性凋亡使永生化上皮细胞高度致瘤性，但这如何受到其他常见肿瘤突变的影响尚不清楚。在凋亡缺陷细胞中，通过AKT激活或beclin 1的等位基因破坏来抑制自噬，通过抑制自噬依赖性存活途径来赋予对代谢应激的敏感性。虽然自噬起到缓冲代谢应激的作用，但细胞凋亡和自噬的组合损伤在体外和体内促进坏死细胞死亡。因此，在营养限制的条件下抑制自噬可以使细胞死亡恢复到难治性肿瘤，但这种坏死与炎症和加速肿瘤生长有关。因此，自噬可能通过减轻代谢应激并与细胞凋亡一起通过防止坏死导致的死亡而在肿瘤抑制中起作用。
Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to metabolic stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer metabolic stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing death by necrosis.