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Genes Dev. 2016 Aug 1;30(15):1704-17. doi: 10.1101/gad.283416.116. Epub 2016 Aug 11.

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

Author information

1
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA; Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854, USA;
2
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA;
3
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA;
4
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA;
5
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA;
6
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.

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.

KEYWORDS:

ROS; Ras-driven cancer; amino acid; autophagy; energy charge; mitochondrial metabolism; nucleotide

PMID:
27516533
PMCID:
PMC5002976
DOI:
10.1101/gad.283416.116
[Indexed for MEDLINE]
Free PMC Article

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