Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids

Jurre J. Kamphorst, Justin R. Cross, Jing Fan, Elisa De Stanchina, Robin Mathew, Eileen P. White, Craig B. Thompson, Joshua D. Rabinowitz

Research output: Contribution to journalArticle

317 Scopus citations

Abstract

Cancer cell growth requires fatty acids to replicate cellular membranes. The kinase Akt is known to up-regulate fatty acid synthesis and desaturation, which is carried out by the oxygen-consuming enzyme stearoyl-CoA desaturase (SCD)1. We used 13C tracers and lipidomics to probe fatty acid metabolism, including desaturation, as a function of oncogene expression and oxygen availability. During hypoxia, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to fatty acid synthesis increases. In addition, we find that hypoxic cells bypass de novo lipogenesis, and thus, both the need for acetyl-CoA and the oxygen-dependent SCD1-reaction, by scavenging serum fatty acids. The preferred substrates for scavenging are phospholipids with one fatty acid tail (lysophospholipids). Hypoxic reprogramming of de novo lipogenesis can be reproduced in normoxic cells by Ras activation. This renders Ras-driven cells, both in culture and in allografts, resistant to SCD1 inhibition. Thus, a mechanism by which oncogenic Ras confers metabolic robustness is through lipid scavenging.

Original languageEnglish (US)
Pages (from-to)8882-8887
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number22
DOIs
StatePublished - May 28 2013

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Isotope tracing
  • Lipid metabolism
  • Lipogenesis in cancer

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