University of Lyon, 69000 Lyon, France.
Mol Cell. 2013 Mar 28;49(6):1049-59. doi: 10.1016/j.molcel.2013.01.009. Epub 2013 Feb 7.
As solid tumors expand, oxygen and nutrients become limiting owing to inadequate vascularization and diffusion. How malignant cells cope with this potentially lethal metabolic stress remains poorly understood. We found that glucose shortage associated with malignant progression triggers apoptosis through the endoplasmic reticulum (ER) unfolded protein response (UPR). ER stress is in part caused by reduced glucose flux through the hexosamine pathway. Deletion of the proapoptotic UPR effector CHOP in a mouse model of K-ras(G12V)-induced lung cancer increases tumor incidence, strongly supporting the notion that ER stress serves as a barrier to malignancy. Overcoming this barrier requires the selective attenuation of the PERK-CHOP arm of the UPR by the molecular chaperone p58(IPK). Furthermore, p58(IPK)-mediated adaptive response enables cells to benefit from the protective features of chronic UPR. Altogether, these results show that ER stress activation and p58(IPK) expression control the fate of malignant cells facing glucose shortage.
随着实体瘤的不断生长，由于血管生成和扩散不足，氧气和营养物质变得有限。恶性细胞如何应对这种潜在的致命代谢应激仍然知之甚少。我们发现，与恶性进展相关的葡萄糖缺乏通过内质网（ER）未折叠蛋白反应（UPR）触发细胞凋亡。ER 应激部分是由通过己糖胺途径的葡萄糖通量减少引起的。在 K-ras(G12V)诱导的肺癌的小鼠模型中，删除促凋亡 UPR 效应物 CHOP，会增加肿瘤的发生率，这强烈支持 ER 应激是恶性肿瘤的障碍这一观点。克服这一障碍需要分子伴侣 p58(IPK)选择性地减弱 UPR 的 PERK-CHOP 臂。此外，p58(IPK)介导的适应性反应使细胞能够从慢性 UPR 的保护特性中受益。总而言之，这些结果表明，ER 应激的激活和 p58(IPK)的表达控制着面临葡萄糖缺乏的恶性细胞的命运。
