Data from Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of <i>Braf</i><sup>V600E</sup>–Driven Lung Tumors

Abstract

<div>Abstract<p>Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene <i>Atg7</i> was deleted in a mouse model of <i>Braf</i><sup>V600E</sup>-induced lung cancer in the presence or absence of the tumor suppressor <i>Trp53</i>. <i>Atg7</i> deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from <i>Nrf2</i> ablation. Compound deletion of <i>Atg7</i> and <i>Nrf2</i> had no additive effect, suggesting that both genes modulate tumorigenesis by regulating oxidative stress and revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, <i>Atg7</i> deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse life span. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire and survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains <i>Braf</i><sup>V600E</sup> tumor growth and metabolism.</p><p><b>Significance:</b> The essential autophagy gene <i>Atg7</i> functions to promote <i>Braf</i><sup>V600E</sup>-driven lung tumorigenesis by preserving mitochondrial glutamine metabolism. This suggests that inhibiting autophagy is a novel approach to treating <i>Braf</i><sup>V600E</sup>-driven cancers. <i>Cancer Discov; 3(11); 1272–85. ©2013 AACR</i>.</p><p>See related commentary by Chen and Guan, p. 1225</p><p>This article is highlighted in the In This Issue feature, p. 1207</p></div>