Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of BrafV600E–Driven Lung Tumors

AM Strohecker, JY Guo, G Karsli-Uzunbas, SM Price… - Cancer discovery, 2013 - AACR
Cancer discovery, 2013AACR
Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves
mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse
model of Braf V600E-induced lung cancer in the presence or absence of the tumor
suppressor Trp53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell
proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7
and Nrf2 had no additive effect, suggesting that both genes modulate tumorigenesis by …
Abstract
Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BrafV600E-induced lung cancer in the presence or absence of the tumor suppressor Trp53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 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, Atg7 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 BrafV600E tumor growth and metabolism.
Significance: The essential autophagy gene Atg7 functions to promote BrafV600E-driven lung tumorigenesis by preserving mitochondrial glutamine metabolism. This suggests that inhibiting autophagy is a novel approach to treating BrafV600E-driven cancers. Cancer Discov; 3(11); 1272–85. ©2013 AACR.
See related commentary by Chen and Guan, p. 1225
This article is highlighted in the In This Issue feature, p. 1207
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