Department of Pathology, University of California, San Francisco Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
Mol Biol Cell. 2011 Jan 15;22(2):165-78. doi: 10.1091/mbc.E10-06-0500. Epub 2010 Nov 30.
The protumorigenic functions for autophagy are largely attributed to its ability to promote cancer cell survival in response to diverse stresses. Here we demonstrate an unexpected connection between autophagy and glucose metabolism that facilitates adhesion-independent transformation driven by a strong oncogenic insult-mutationally active Ras. In cells ectopically expressing oncogenic H-Ras as well as human cancer cell lines harboring endogenous K-Ras mutations, autophagy is induced following extracellular matrix detachment. Inhibiting autophagy due to the genetic deletion or RNA interference-mediated depletion of multiple autophagy regulators attenuates Ras-mediated adhesion-independent transformation and proliferation as well as reduces glycolytic capacity. Furthermore, in contrast to autophagy-competent cells, both proliferation and transformation in autophagy-deficient cells expressing oncogenic Ras are insensitive to reductions in glucose availability. Overall, increased glycolysis in autophagy-competent cells facilitates Ras-mediated adhesion-independent transformation, suggesting a unique mechanism by which autophagy may promote Ras-driven tumor growth in specific metabolic contexts.
自噬的促肿瘤功能主要归因于其在应对各种应激时促进癌细胞存活的能力。在这里，我们证明了自噬与葡萄糖代谢之间存在意想不到的联系，这种联系有助于由强烈致癌刺激——突变激活的 Ras 驱动的非黏附依赖性转化。在过表达致癌 H-Ras 的细胞以及携带内源性 K-Ras 突变的人类癌细胞系中，细胞外基质脱离后会诱导自噬。由于遗传缺失或 RNA 干扰介导的多种自噬调节剂的消耗而抑制自噬，会减弱 Ras 介导的非黏附依赖性转化和增殖，并降低糖酵解能力。此外，与自噬功能正常的细胞相比，表达致癌 Ras 的自噬缺陷细胞的增殖和转化均不受葡萄糖供应减少的影响。总的来说，自噬功能正常的细胞中糖酵解的增加促进了 Ras 介导的非黏附依赖性转化，这表明自噬可能在特定代谢环境中通过一种独特的机制促进 Ras 驱动的肿瘤生长。
