Abstract
There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K–AKT–mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5. Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.
Funder
National Institutes of Health
Oregon Health and Science University-Knight Cancer Institute
Hope Foundation
SWOG [Southwest Oncology Group]
Oregon Translational Research and Development Institute
West Coast Metabolomics Core (WCMC) Pilot
Kure It Cancer Research
National Institute of General Medical Sciences
NIH
Department of Defense
Prostate Cancer Research Program
Prostate Cancer Foundation
New Jersey Health Foundation
DOD Prostate Cancer Research Program
National Cancer Institute
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
56 articles.
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