Oncogene-induced senescence results in marked metabolic and bioenergetic alterations

Celia Quijano, Liu Cao, Maria M. Fergusson, Hector Romero, Jie Liu, Sarah Gutkind, Ilsa I. Rovira, Robert P. Mohney, Edward D. Karoly, Toren Finkel

Research output: Contribution to journalArticle

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 presenescent 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.

Original languageEnglish (US)
Pages (from-to)1383-1392
Number of pages10
JournalCell cycle (Georgetown, Tex.)
Volume11
Issue number7
DOIs
Publication statusPublished - Apr 1 2012
Externally publishedYes

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Keywords

  • Fatty acid oxidation
  • Metabolomics
  • Oncogene-induced senescence
  • Ras

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Quijano, C., Cao, L., Fergusson, M. M., Romero, H., Liu, J., Gutkind, S., ... Finkel, T. (2012). Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell cycle (Georgetown, Tex.), 11(7), 1383-1392. https://doi.org/10.4161/cc.19800