title: Oncogene-induced senescence results in marked metabolic and bioenergetic alterations.
abstract: Oncogene-induced senescence (OIS) is characterized by permanent growth arrest and the acquisition of a secretory, pro-inflammatory state. Increasingly, OIS is viewed as an important barrier to tumorgenesis. Surprisingly, relatively little is known about the metabolic changes that accompany and therefore may contribute to OIS. Here, we have performed a metabolomic and bioenergetic analysis of Ras-induced senescence. Profiling approximately 300 different intracellular metabolites reveals that cells that have undergone OIS develop a unique metabolic signature that differs markedly from cells undergoing replicative senescence. A number of lipid metabolites appear uniquely increased in OIS cells, including a marked increase in the level of certain intracellular long chain fatty acids. Functional studies reveal that this alteration in the metabolome reflects substantial changes in overall lipid metabolism. In particular, Ras-induced senescent cells manifest a decline in lipid synthesis and a significant increase in fatty acid oxidation. Increased fatty acid oxidation results in an unexpectedly high rate of basal oxygen consumption in cells that have undergone OIS. Pharmacological or genetic inhibition of carnitine palmitoyltransferase 1, the rate-limiting step in mitochondrial fatty acid oxidation, restores a pre-senescent metabolic rate and, surprisingly, selectively inhibits the secretory, pro-inflammatory state that accompanies OIS. Thus, Ras-induced senescent cells demonstrate profound alterations in their metabolic and bioenergetic profiles, particularly with regards to the levels, synthesis and oxidation of free fatty acids. Furthermore, the inflammatory phenotype that accompanies OIS appears to be related to these underlying changes in cellular metabolism.
authors.affiliation: Center for Molecular Medicine, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Quijano
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fergusson
authors.forename: Hector
authors.initials: H
authors.lastname: Romero
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Sarah
authors.initials: S
authors.lastname: Gutkind
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D004734:Energy Metabolism / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D055432:Metabolomics / Q000379:methods; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D010101:Oxygen Consumption
chemical_list: D016207:Cytokines; D002334:Carnitine O-Palmitoyltransferase; D015689:Oncogene Protein p21(ras)