Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade

Hui Wen Lue, Jennifer Podolak, Kevin Kolahi, Larry Cheng, Soumya Rao, Devin Garg, Chang Hui Xue, Juha K. Rantala, Jeffrey Tyner, Kent Thornburg, Ann Martinez-Acevedo, Jen-Jane Liu, Christopher Amling, Charles Truillet, Sharon M. Louie, Kimberly E. Anderson, Michael J. Evans, Valerie B. O’Donnell, Daniel K. Nomura, Justin M. DrakeAnna Ritz, George Thomas

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2067-2084
Number of pages18
JournalGenes and Development
Volume31
Issue number20
DOIs
StatePublished - Oct 15 2017

Keywords

  • Autophagy
  • Cancer
  • Metabolism
  • Phospholipid
  • Resistance
  • Signaling

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Lue, H. W., Podolak, J., Kolahi, K., Cheng, L., Rao, S., Garg, D., Xue, C. H., Rantala, J. K., Tyner, J., Thornburg, K., Martinez-Acevedo, A., Liu, J-J., Amling, C., Truillet, C., Louie, S. M., Anderson, K. E., Evans, M. J., O’Donnell, V. B., Nomura, D. K., ... Thomas, G. (2017). Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. Genes and Development, 31(20), 2067-2084. https://doi.org/10.1101/gad.305292.117