Document Detail

Oncogene-induced senescence results in marked metabolic and bioenergetic alterations.
MedLine Citation:
PMID:  22421146     Owner:  NLM     Status:  MEDLINE    
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.
Celia Quijano; Liu Cao; Maria M Fergusson; Hector Romero; Jie Liu; Sarah Gutkind; Ilsa I Rovira; Robert P Mohney; Edward D Karoly; Toren Finkel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2012-04-01
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-20     Completed Date:  2013-01-04     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1383-92     Citation Subset:  IM    
Center for Molecular Medicine, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
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MeSH Terms
Carnitine O-Palmitoyltransferase / antagonists & inhibitors,  metabolism
Cell Aging / genetics*
Cell Line, Tumor
Cell Proliferation
Cytokines / biosynthesis
Energy Metabolism / genetics*
Gene Expression Profiling
Inflammation / genetics
Lipid Metabolism / genetics*
Metabolomics / methods
Oncogene Protein p21(ras) / genetics,  metabolism
Oxygen Consumption
Reg. No./Substance:
0/Cytokines; EC O-Palmitoyltransferase; EC Protein p21(ras)
Comment In:
Cell Cycle. 2012 Apr 1;11(7):1271-2   [PMID:  22426417 ]

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