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A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.

ABSTRACT: At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-?-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying a similar phenotype. Senescence is considered a DNA damage response, but cellular heterogeneity has frustrated identification of senescence-specific markers and targets. To explore the senescent cell proteome, we treated tumor cells with etoposide and enriched SA-?-GalHI cells by fluorescence-activated cell sorting (FACS). The enriched TIS cells were compared to proliferating or quiescent cells by label-free quantitative LC-MS/MS proteomics and systems analysis, revealing activation of multiple lipid metabolism pathways. Senescent cells accumulated lipid droplets and imported lipid tracers, while treating proliferating cells with specific lipids induced senescence. Senescent cells also displayed increased lipid aldehydes and upregulation of aldehyde detoxifying enzymes. These results place deregulation of lipid metabolism alongside genotoxic stress as factors regulating cellular senescence.

SUBMITTER: Flor AC

PROVIDER: S-EPMC5661608 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.

Flor Amy C AC Wolfgeher Don D Wu Ding D Kron Stephen J SJ

Cell death discovery 20171030

At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-<i>β</i>-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying a similar phenotype. Senescence is considered a DNA damage response, but cellular heterogeneity has frustrated identification of senescence-specific markers and targets. To explore the senescen ...[more]

PMID: 29090099

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Project description:The aim of this study was to identify the cardiac oxidoreductases involved in the metabolism of 4-hydroxy-2-trans-nonenal (HNE), an alpha,beta unsaturated aldehyde generated during the peroxidation of omega-6 polyunsaturated fatty acids. In homogenates of bovine, human and rat ventricles the primary pyridine coenzyme-linked metabolism of HNE was associated with NADPH oxidation. The NADPH-dependent enzyme catalysing HNE reduction was purified to homogeneity from bovine heart. The purified enzyme displayed kinetic and immunological properties identical with the polyol pathway enzyme aldose reductase (AR), and catalysed the reduction of HNE to its alcohol 1,4-dihydroxynonene (DHN), with a Km of 7+/-2 microM. In the presence of NADP the enzyme did not catalyse the oxidation of DHN. During catalysis, HNE did not cause inactivation of AR. Nevertheless when the apoenzyme was incubated with HNE a dissociable complex was formed between the enzyme and HNE, followed by irreversible loss of activity. Inactivation of the enzyme by HNE was prevented by NADP. Partial modification of the enzyme with HNE led to a 17-fold increase in the KHNEm and Kglyceraldehydem, and the HNE-modified enzyme had a 500-fold higher IC50 for sorbinil than for the reduced enzyme, whereas the IC50 for tolrestat increased 25-fold. Incubation of the enzyme with radiolabelled HNE resulted in the incorporation of 2 mol of the aldehyde per mol of the enzyme. Sequence analysis of the radiolabelled peptides revealed modification of Cys-298 and Cys-187. The amino acid sequence of the HNE-modified peptides confirmed that the HNE-reducing cardiac enzyme is AR and not a related protein such as the fibroblast-growth-factor-regulated protein FR-1 or the mouse vas deferens protein MVDP. These results indicate that AR represents the only major oxidoreductase in the heart capable of utilizing HNE. The high affinity of the enzyme for HNE, the lack of inactivation during catalysis, and the lack of significant alcohol dehydrogenase activity of the protein suggests that AR-mediated catalysis of HNE is unlikely to be limited by substrate/product inhibition. Thus AR might constitute an antioxidative enzyme involved in myocardial protection against endogenous and exogenous cytotoxic aldehydes and against oxidative stress.

Dataset Information

A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.

Publications

A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.

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