Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis

The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
Genes & Development (Impact Factor: 10.8). 07/2013; 27(13):1447-61. DOI: 10.1101/gad.219642.113
Source: PubMed


Macroautophagy (autophagy hereafter) degrades and recycles proteins and organelles to support metabolism and survival in starvation. Oncogenic Ras up-regulates autophagy, and Ras-transformed cell lines require autophagy for mitochondrial function, stress survival, and engrafted tumor growth. Here, the essential autophagy gene autophagy-related-7 (atg7) was deleted concurrently with K-ras(G12D) activation in mouse models for non-small-cell lung cancer (NSCLC). atg7-deficient tumors accumulated dysfunctional mitochondria and prematurely induced p53 and proliferative arrest, which reduced tumor burden that was partly relieved by p53 deletion. atg7 loss altered tumor fate from adenomas and carcinomas to oncocytomas-rare, predominantly benign tumors characterized by the accumulation of defective mitochondria. Surprisingly, lipid accumulation occurred in atg7-deficient tumors only when p53 was deleted. atg7- and p53-deficient tumor-derived cell lines (TDCLs) had compromised starvation survival and formed lipidic cysts instead of tumors, suggesting defective utilization of lipid stores. atg7 deficiency reduced fatty acid oxidation (FAO) and increased sensitivity to FAO inhibition, indicating that with p53 loss, Ras-driven tumors require autophagy for mitochondrial function and lipid catabolism. Thus, autophagy is required for carcinoma fate, and autophagy defects may be a molecular basis for the occurrence of oncocytomas. Moreover, cancers require autophagy for distinct roles in metabolism that are oncogene- and tumor suppressor gene-specific.

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    • "Of note, autophagic responses are negatively regulated by mechanistic target of rapamycin (MTOR) complex I (MTORCI), a key hub for the control of cell survival, growth and proliferation (Laplante & Sabatini, 2012). Autophagy plays a major role in the differentiation and function of adipocytes (Singh et al, 2009b; Zhang et al, 2009), in the mobilization of lipid droplets within hepatocytes (a process that has been dubbed " lipophagy " ) (Singh et al, 2009a), as well as in the oxidation of fatty acids (FAs) by cancer cells (Guo et al, 2013), underscoring its significant impact on lipid metabolism. Conversely, several saturated FAs (SFAs) and unsaturated FAs (UFAs) appear to modulate autophagy (Brenner et al, 2013). "
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