title: Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids.
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 (13)C 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.
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Jurre J
authors.initials: JJ
authors.lastname: Kamphorst
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Robin
authors.initials: R
authors.lastname: Mathew
authors.forename: Eileen P
authors.initials: EP
authors.lastname: White
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D002247:Carbon Isotopes / Q000737:chemistry; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D005947:Glucose / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D010873:Pinocytosis / Q000502:physiology; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D002247:Carbon Isotopes; D005227:Fatty Acids; D010743:Phospholipids; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D005973:Glutamine; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; D018631:ras Proteins; D005947:Glucose
keywords: isotope tracing; lipid metabolism; lipogenesis in cancer