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.
Bibliographical noteFunding Information:
We thank Andrew Thorburn, Katherine Ellwood-Yen, and Gary Thomas for helpful discussion; Jay Debnath for the ATG5+/+ and ATG5−/− MEFs; Ernest Frankel, Emek Demir, and Ozgun Ba-bur for computational advice; Steve Kazmierczak for biochemical analysis; Angela Fleischman for clinical input; Mandy Burns and Ashley Sager for administrative support; Moya Costello and Justin Lallo for artwork; the Histopathology Shared Resource for pathology support; the Massively Parallel Sequencing Shared Resource and Integrated Genomics Shared Resource for genomics support; the Bioanalytical Shared Resource/Pharmacokinetic Core for eicosanoid profiling studies; and the Oregon Translational Research and Development Institute (OTRADI) for high-throughput drug screening support. This study was supported by National Institutes of Health (NIH) grants R01 CA169172, P30 CA069533, and P30 CA069533 13S5 through the Oregon Health and Science University-Knight Cancer Institute, the Hope Foundation (SWOG [Southwest Oncology Group]), the Oregon Translational Research and Development Institute (OTRADI), West Coast Metabolomics Core (WCMC) Pilot, and Kure It Cancer Research (G.V.T.). L.C. is supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339. J.M.D. is supported by the Department of Defense (DOD) Prostate Cancer Research Program (W81XWH-15-1-0236), Prostate Cancer Foundation Young Investigator Award, and a grant from the New Jersey Health Foundation. V.B.O. is a European Research Council Investigator (LipidArrays) and Royal Society Wolfson Research Merit Award Holder. M.J.E. was supported by the Prostate Cancer Foundation Young Investigator Award, the DOD Prostate Cancer Research Program (W81XWH-15-1-0552), and the National Cancer Institute (R00CA172695 and R01CA176671). C.T. was supported by the DOD Prostate Cancer Research Program (W81XWH-16-1-0435).