Defective autophagy control by the p53 rheostat in cancer
Defective autophagy control by the p53 rheostat in cancer
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DOI：
10.4161/cc.9.2.10493
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发表时间：
2010-01-15
期刊：
影响因子：
4.3
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Galluzzi, Lorenzo;Morselli, Eugenia;Kroemer, Guido
自噬是一种调节精细的溶酶体分解代谢途径，有助于长寿蛋白的周转和消除陈旧/受损的细胞器。自噬通过：(1)限制染色体的不稳定性；(2)减少潜在的诱变氧化应激；(3)抑制肿瘤内坏死和局部炎症，真正发挥了抑制作用。自噬缺陷构成了癌细胞的一个特征：(1)提供自主生长信号；(2)对抗增殖刺激不敏感；(3)细胞凋亡被禁止；(4)无限复制；(5)血管生成因子的产生；(6)组织侵袭和转移；(7)避免免疫反应；以及(8)合成代谢增强。P53是人类最著名的肿瘤抑制蛋白，在超过50%的人类癌症中观察到其遗传/表观遗传失活。P53主要通过反式激活促凋亡基因和细胞周期抑制基因来调节肿瘤抑制，但也通过以转录独立的方式促进线粒体凋亡，通过调节代谢回路和调节自噬来调节肿瘤抑制。同时取消其促凋亡和自噬抑制功能的p53突变(或表观遗传学变化)表现为“多发”事件，而不是只影响p53系统的经典(促凋亡和/或细胞周期抑制)功能的“单发”突变。我们推测，在后一种情况下，导致自噬丧失的额外遗传/表观遗传事件可能有助于加速肿瘤发生。
Autophagy is a finely regulated, lysosomal catabolic pathway that contributes to the turnover of long-lived proteins and to the elimination of old/ damaged organelles. Autophagy exerts bona fide oncosuppressive functions by: (1) limiting chromosomal instability; (2) reducing potentially mutagenic oxidative stress; and (3) restraining intratumoral necrosis and local inflammation. Defective autophagy constitutes a hallmark of cancer cells together with: (1) provision of autonomous growth signals;, (2) insensitivity to antiproliferative stimuli; (3) disabled apoptosis; (4) limitless replication; (5) production of angiogenic factors; (6) tissue invasion with metastasis; (7) avoidance of the immune response; and (8) enhanced anabolism. p53 is the best-known human oncosuppressor protein, and its genetic/epigenetic inactivation has been observed in more than 50% of all human cancers. p53 mostly mediates tumor suppression by transactivating pro-apoptotic and cell cycle arresting genes, but also by favoring mitochondrial apoptosis in a transcription-independent fashion, by modulating metabolic circuitries and by regulating autophagy. p53 mutations (or epigenetic changes) that simultaneously abolish its pro-apoptotic and autophagy-inhibitory functions behave as "multi-hit" events, as opposed to "single-hit" mutations that only affect the classical (pro-apoptotic and/or cell cycle-arresting) functions of the p53 system. We speculate that, in this latter case, additional genetic/epigenetic events resulting in disabled autophagy are likely to contribute to accelerated oncogenesis.