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

15 Citations (Scopus)

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

Fingerprint

Cell Survival
Autophagy
Phospholipases A2
Oxidative Phosphorylation
Neoplasms
Lysophospholipids
Essential Genes
Glycolysis
Phosphatidylinositol 3-Kinases
Nonesterified Fatty Acids
Oxidation-Reduction
Mitochondria
Respiration
Homeostasis
Fatty Acids
Maintenance
Apoptosis
Food
Therapeutics
Growth

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. / Lue, Hui Wen; Podolak, Jennifer; Kolahi, Kevin; Cheng, Larry; Rao, Soumya; Garg, Devin; Xue, Chang Hui; Rantala, Juha K.; Tyner, Jeffrey; Thornburg, Kent; Martinez-Acevedo, Ann; Liu, Jen-Jane; Amling, Christopher; Truillet, Charles; Louie, Sharon M.; Anderson, Kimberly E.; Evans, Michael J.; O’Donnell, Valerie B.; Nomura, Daniel K.; Drake, Justin M.; Ritz, Anna; Thomas, George.

In: Genes and Development, Vol. 31, No. 20, 15.10.2017, p. 2067-2084.

Research output: Contribution to journalArticle

Lue, HW, Podolak, J, Kolahi, K, Cheng, L, Rao, S, Garg, D, Xue, CH, Rantala, JK, Tyner, J, Thornburg, K, Martinez-Acevedo, A, Liu, J-J, Amling, C, Truillet, C, Louie, SM, Anderson, KE, Evans, MJ, O’Donnell, VB, Nomura, DK, Drake, JM, Ritz, A & Thomas, G 2017, 'Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade', Genes and Development, vol. 31, no. 20, pp. 2067-2084. https://doi.org/10.1101/gad.305292.117
Lue, Hui Wen ; Podolak, Jennifer ; Kolahi, Kevin ; Cheng, Larry ; Rao, Soumya ; Garg, Devin ; Xue, Chang Hui ; Rantala, Juha K. ; Tyner, Jeffrey ; Thornburg, Kent ; Martinez-Acevedo, Ann ; Liu, Jen-Jane ; Amling, Christopher ; Truillet, Charles ; Louie, Sharon M. ; Anderson, Kimberly E. ; Evans, Michael J. ; O’Donnell, Valerie B. ; Nomura, Daniel K. ; Drake, Justin M. ; Ritz, Anna ; Thomas, George. / Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. In: Genes and Development. 2017 ; Vol. 31, No. 20. pp. 2067-2084.
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