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Oncogene-induced senescence results in marked metabolic and bioenergetic alterations
Open accessAbstract
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.
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“Senescent cells are hypermetabolic; that is, they have enhanced oxygen consumption, and use glycolysis, fatty acid oxidation and oxidative phosphorylation in an aberrant manner to maximize energy production, which is needed to maintain ATP- consuming homeostatic processes 45,55,56 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [55]
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“For example, lipid metabolites vary significantly between oncogene-induced senescence and replicative senescence (Quijano et al., 2012).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Quijano et al., 2012
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“Quijano et al. 53 showed that the inhibition of FA oxidation in OIS cells results in a reduced production of many SASP components.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [53]
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“Quijano et al. 53 showed that HRAS-G12V-induced senescent HDFs exhibit reduced lipid synthesis and increased fatty acid (FA) oxidation, leading to enhanced mitochondrial oxygen consumption.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [53]
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“Moreover, during OIS, fatty acid metabolism is altered, glucose consumption is enhanced, and the utilization of pyruvate in the tricarboxylic acid cycle and nucleotide deficiency are increased [119,216,217,218,219].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [216]
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Metadata
- Authors
- Quijano, C., Cao, L., Fergusson, M. M., Romero, H., Liu, J., Gutkind, S., Rovira, I. I., Mohney, R. P., Karoly, E. D., & Finkel, T.
- Affiliations
- National Institutes of Health (US)
- Universidad de la República de Uruguay (UY)
- Metabolon (United States) (US)
- Corresponding author
- Finkel, Toren
- ORCID
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2012-04
- Volume
- 11
- Issue
- 7
- Pages
- 1383-1392
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC3350879
- OpenAlex
- W1997142695
- Cited by
- 155
- References
- 50
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 18 · 2023: 13 · 2022: 11 · 2021: 14 · 2020: 12 · 2019: 16 · 2018: 11 · 2017: 7 · 2016: 12 · 2015: 7 · 2014: 5 · 2013: 2 · 2012: 2
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- oncogene-induced senescence, Ras-induced senescence, cellular metabolism, bioenergetics, lipid metabolism, fatty acid oxidation, lipogenesis, long-chain fatty acids, carnitine palmitoyltransferase 1, oxygen consumption, replicative senescence, senescence-associated secretory phenotype, inflammation, metabolomics
- MeSH terms
- Carnitine O-Palmitoyltransferase, Energy Metabolism, Humans, Inflammation, Oncogenes, Oxygen Consumption, Oncogene Protein p21(ras), Cytokines, Cellular Senescence, Gene Expression Profiling, Cell Line, Tumor, Cell Proliferation, Lipid Metabolism, Metabolomics
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