ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth
ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth
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DOI：
10.1172/jci62973
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发表时间：
2012-12-01
影响因子：
15.9
通讯作者：
Koumenis, Constantinos
中科院分区：
文献类型：
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作者：
Hart, Lori S.;Cunningham, John T.;Koumenis, Constantinos
原癌基因c-Myc矛盾地同时激活了增殖和凋亡。在致病状态下，c-Myc诱导的细胞凋亡通过一种关键但鲜为人知的逃逸机制被绕过，这种逃逸机制促进了细胞转化和肿瘤的发生。内质网中未折叠蛋白的积累启动了一种称为未折叠蛋白反应(UPR)的细胞应激程序，以支持细胞生存。对自发性小鼠和人类淋巴瘤的分析表明，与正常组织相比，UPR的激活水平明显更高。利用多种遗传模型，我们证明了c-Myc和N-Myc激活了UPR的PERK/eIF2α/ATF4臂，通过诱导细胞保护性自噬而导致细胞存活率增加。抑制PERK可显著减少Myc诱导的自噬、克隆形成和肿瘤形成。此外，药物或遗传抑制自噬会导致Myc依赖的细胞凋亡增加。从机制上讲，我们证明了Myc依赖的蛋白质合成增加和UPR激活之间的重要联系。具体地说，通过使用小鼠微小(L24(+/-))突变体，导致野生型蛋白质合成水平和Myc诱导的淋巴肿大减弱，我们表明Myc诱导的UPR激活被逆转。我们的发现确立了UPR作为c-Myc诱导转化的增强剂的作用，并提示UPR抑制可能对以c-Myc过表达为特征的恶性肿瘤特别有效。
The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2 alpha/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24(+/-)) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.