Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells.

TitleAutophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsGuo, JYanxiang, Teng, X, Laddha, SV, Ma, S, Van Nostrand, SC, Yang, Y, Khor, S, Chan, CS, Rabinowitz, JD, White, E
JournalGenes Dev
Volume30
Issue15
Pagination1704-17
Date Published2016 Aug 01
ISSN1549-5477
Abstract

Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7(-/-)) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.

DOI10.1101/gad.283416.116
Alternate JournalGenes Dev.
PubMed ID27516533
PubMed Central IDPMC5002976
Grant ListP30 CA072720 / CA / NCI NIH HHS / United States
R01 CA193970 / CA / NCI NIH HHS / United States
K22 CA190521 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R01 CA130893 / CA / NCI NIH HHS / United States
R01 CA188096 / CA / NCI NIH HHS / United States