Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 15, 2017
- Source ID
- 10.1101/gad.305292.117
Entities
People
- Ann Martinez-acevedo
- Anna Ritz
- Chang-hui Xue
- Charles Truillet
- Christopher L. Amling
- Daniel Nomura
- Devin Garg
- George V Thomas
- Hui-wen Lue
- Jeffrey W. Tyner
- Jen-jane Liu
- Jennifer Podolak
- Juha K. Rantala
- Justin M Drake
- Kent L. Thornburg
- Kevin Kolahi
- Kimberly E. Anderson
- Larry C Cheng
- Michael J. Evans
- Sharon M. Louie
- Soumya Rao
- Valerie B. O'donnell
Organizations
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institutes of Health
- New Jersey Health Foundation
- Prostate Cancer Foundation
- United States Department of Defense