Shift in sphingolipid metabolism leads to an accumulation of ceramide in senescence

Venable, Mark E.; Webb-Froehlich, Lisa M.; Sloan, Eldon F.; Thomley, Jill E.

doi:10.1016/j.mad.2006.01.003

Cited by 39 publications

(25 citation statements)

References 36 publications

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“…In confluent MCF7 cells, neutral SMase moved from the cytosol to the plasma membrane, with a concomitant increase in long-chain ceramides and senescence induction. Senescent cells have also been found to have altered sphingolipid metabolisms, with increased glycosylceramide production at the expense of sphingomyelin (16). In WI-38 human diploid fibroblasts (11,17), Molt-4 human leukemia (18) and A549 human lung carcinoma (19,20), exogenous C 6 -ceramide was able to block cell cycle progression in the G 0 -G 1 phase.…”

Section: Discussionmentioning

confidence: 99%

Ceramide Regulates Gemcitabine-Induced Senescence and Apoptosis in Human Pancreatic Cancer Cell Lines

Modrak

Leon

Goldenberg

et al. 2009

Molecular Cancer Research

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Bioactive sphingolipids are potent intracellular signaling molecules having profound effects on cell death, growth, and differentiation. Pharmacologic manipulation of sphingolipid levels could have a significant effect on the induction of apoptosis by anticancer agents, and thus, improve treatment efficacy. We observed that gemcitabine cannot completely kill AsPc1 and Panc1 human pancreatic cancer cells in culture; even at high concentrations of gemcitabine, 30% to 40% of the cells remain viable. By adding sphingomyelin to the culture medium, gemcitabineinduced cell death increased synergistically to >90%. Panc1 cells that survived high concentrations of gemcitabine had an increase in β-galactosidase activity, a marker of senescence. The inclusion of sphingomyelin with gemcitabine reduced β-galactosidase activity, as compared with cells treated with gemcitabine alone. Expression of p21 waf1/cip1 in both cell lines exposed to sphingomyelin, gemcitabine, and gemcitabine + sphingomyelin varied relative to the untreated group. C 8 -ceramide induced both cell death and senescence in a dose-dependent manner. These results indicate that gemcitabine induces senescence in pancreatic cancer cells and that sphingomyelin-enhanced chemosensitivity is achieved through reducing the induction of senescence by redirecting the cell to enter the apoptotic pathway. Ceramide levels seem to be critical to this decision, with cell cycle progression being uninhibited at low ceramide levels, senescence induced at moderate levels, and apoptosis initiated at high levels. Our results provide further evidence that targeting the sphingolipid metabolism is a means of enhancing the efficacy of chemotherapeutic agents. (Mol Cancer Res 2009;7(6):890-6)

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Section: Discussionmentioning

confidence: 99%

Ceramide Regulates Gemcitabine-Induced Senescence and Apoptosis in Human Pancreatic Cancer Cell Lines

Modrak

Leon

Goldenberg

et al. 2009

Molecular Cancer Research

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“…24 Ceramide also increases when endothelial cells undergo replicative senescence. 47,133 Senescence-enhanced oxidative stress appears to be associated with decreased expression of mitochondrial cytochrome c oxidase by vascular endothelial cells. 20,134 Altered expression of other mitochondrial genes has also been reported and may participate in endothelial cell senescence.…”

Section: Oxidative Stress Mitochondria and Dna Damagementioning

confidence: 99%

Vascular Cell Senescence

Minamino

Komuro

2007

Circulation Research

470

221

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Abstract-Cardiologists and most physicians believe that aging is an independent risk factor for human atherosclerosis, whereas atherosclerosis is thought to be a characteristic feature of aging in humans by many gerontologists. Because atherosclerosis is among the age-associated changes that almost always escape the influence of natural selection in humans, it might be reasonable to regard atherosclerosis as a feature of aging. Accordingly, when we investigate the pathogenesis of human atherosclerosis, it may be more important to answer the question of how we age than what specifically promotes atherosclerosis. Recently, genetic analyses using various animal models have identified molecules that are crucial for aging. These include components of the DNA-repair system, the tumor suppressor pathway, the telomere maintenance system, the insulin/Akt pathway, and other metabolic pathways. Interestingly, most of the molecules that influence the phenotypic changes of aging also regulate cellular senescence, suggesting a causative link between cellular senescence and aging. For example, DNA-repair defects can cause phenotypic changes that resemble premature aging, and senescent cells that show DNA damage accumulate in the elderly. Excessive calorie intake can cause diabetes and hyperinsulinemia, whereas dysregulation of the insulin pathway has been shown to induce cellular senescence in vitro. Calorie restriction or a reduction of insulin signals extends the lifespan of various species and decreases biomarkers of cellular senescence in vivo. There is emerging evidence that cellular senescence contributes to the pathogenesis of human atherosclerosis. Senescent vascular cells accumulate in human atheroma tissues and exhibit various features of dysfunction. In this review, we examine the hypothesis that cellular senescence might contribute to atherosclerosis, which is a characteristic of aging in humans. (Circ Res. 2007;100:15-26.)

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“…Ceramides (CERs) not only have physicochemical roles as a barrier against cell permeability and as a matrix for the association of membrane proteins but also have physiological roles in signal transduction and cell regulation relevant to apoptosis, cell growth arrest, differentiation, senescence, and immune responses (1)(2)(3)(4). Compared with other human cells/tissues, the stratum corneum (SC) of human skin has extremely complex CERs consisting of fatty acid moieties (nonhydroxy, a-hydroxy, or ester-linked v-hydroxy) and sphingoid moieties (sphingosine, dihydrosphingosine, phytosphingosine, or 6-hydroxy-sphingosine) (5).…”

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confidence: 99%

Characterization of overall ceramide species in human stratum corneum

Masukawa

Narita

Shimizu

et al. 2008

Journal of Lipid Research

299

259

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Ceramides (CERs) in human stratum corneum (SC) play physicochemical roles in determining barrier and waterholding functions of the skin, and specific species might be closely related to the regulation of keratinization, together with other CER-related lipids. Structures of those diverse CER species, however, have not been comprehensively revealed. The aim of this study was to characterize overall CER species in the SC. First, we constructed 3D multi-mass chromatograms of the overall CER species, based on normalphase liquid chromatography (NPLC) connected to electrospray ionization-mass spectrometry (ESI-MS) using a gradient elution system and a postcolumn addition of a volatile saltcontaining polar solvent. The CERs targeted from the 3D chromatograms were structurally analyzed using NPLC-ESItandem mass spectrometry (MS/MS), which resulted in the identification of 342 CER species in the inner forearm SC. This led to the discovery of a new CER class consisting of ahydroxy fatty acid and dihydrosphingosine moieties, in addition to the 10 classes generally known. The results also revealed that those CERs contain long-chain (more than C 18 )-containing sphingoids and a great number of isobaric species. These novel results will contribute not only to physiochemical research on CERs in the SC but also to lipidomics approaches to CERs in the skin.-Masukawa, Y

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Shift in sphingolipid metabolism leads to an accumulation of ceramide in senescence

Cited by 39 publications

References 36 publications

Ceramide Regulates Gemcitabine-Induced Senescence and Apoptosis in Human Pancreatic Cancer Cell Lines

Ceramide Regulates Gemcitabine-Induced Senescence and Apoptosis in Human Pancreatic Cancer Cell Lines

Vascular Cell Senescence

Characterization of overall ceramide species in human stratum corneum

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