Autophagy suppresses tumor progression by limiting chromosomal instability
Autophagy suppresses tumor progression by limiting chromosomal instability
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DOI：
10.1101/gad.1545107
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发表时间：
2007-06-01
影响因子：
10.5
通讯作者：
White, Eileen
中科院分区：
文献类型：
--
作者：
Mathew, Robin;Kongara, Sameera;White, Eileen
自噬是一种大量降解过程，可促进代谢应激下的生存，但如果执行完成，它也可能成为细胞死亡的一种手段。重要自噬基因 beclin1 的单等位基因缺失会导致对代谢应激的易感性，同时也会促进肿瘤发生。这就提出了一个悖论，即生存途径的丧失会促进肿瘤生长，但确切的机制尚不清楚。在这里，我们发现受损的自噬促进了染色体不稳定。未能通过自噬维持代谢与 DNA 损伤、基因扩增和非整倍性增加有关，而这种基因组不稳定性可能会促进肿瘤发生。因此，自噬在代谢应激期间维持新陈代谢和生存，从而保护基因组，这为生存途径的丧失如何导致肿瘤进展提供了解释。自噬的这种新作用的鉴定对于合理化疗和自噬诱导剂作为潜在化学预防剂的治疗开发可能很重要。
Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.