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

Kamphorst, J.J. , Cross, J.R., Fan, J., de Stanchina, E., Mathew, R., White, E.P., Thompson, C.B. and Rabinowitz, J.D. (2013) Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proceedings of the National Academy of Sciences of the United States of America, 110(22), pp. 8882-8887. (doi:10.1073/pnas.1307237110)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kamphorst, Dr Jurre
Authors: Kamphorst, J.J., Cross, J.R., Fan, J., de Stanchina, E., Mathew, R., White, E.P., Thompson, C.B., and Rabinowitz, J.D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490

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