Mitochondria and ceramide: intertwined roles in regulation of apoptosis

Birbes, Hélène; Bawab, Samer El; Obeid, Lina M.; Hannun, Yusuf A.

doi:10.1016/s0065-2571(01)00026-7

Cited by 140 publications

(96 citation statements)

References 108 publications

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“…A sustained decrease in Dc m was also observed in response to the poly-drug treatment of SQ20B and SCC61 cells. Experiments conducted on different radiosensitive cell lines also confirm that exogenous (Decaudin et al, 1998;Ghafourifar et al, 1999) or endogenous ceramide (Tepper et al, 1999;Thomas et al, 1999;Rodriguez-Lafrasse et al, 2001;Alphonse et al, 2002) can directly trigger the loss of Dc m (Birbes et al, 2002). The present work confirms that endogenous ceramide can induce apoptosis via a caspasedependent transduction pathway, in agreement with previous reports (Ito et al, 1999;Tepper et al, 1999;Thomas et al, 1999;Alphonse et al, 2002).…”

Section: Discussionsupporting

confidence: 92%

Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

et al. 2004

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Section: Discussionsupporting

confidence: 92%

Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

et al. 2004

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“…This may be of special interest in the development of new means to treat cancer in which drug-activated SMases may provide for greater sensitivity of the tumor cells to induction of apoptosis by other agents. It has also been shown that subcellular compartmentalization of ceramide production, such as in the nucleus versus the mitochondria versus plasma membrane versus endoplasmic reticulum, has a role in the biological effect of ceramide production (12,22,23). Thus, intracellular ceramide levels are controlled by a complex integration of biosynthetic/catabolic, spatial, and temporal mechanisms which can lead to several alternative biological outcomes.…”

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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“…Studies have identified mitochondrial presence of enzymes and metabolites thereof involved in a mitochondrial network of sphingolipid metabolism (45)(46)(47). In addition, mitochondrial targeting of bacterial SMase was the only intracellular location where transfection-induced ceramide formation positively correlated with the induction of apoptosis (47,48). Furthermore, BcR cross-linking has been shown to up-regulate the enzyme CPT-I, which catalyzes import of fatty acids used for ␤-oxidation into mitochondria (49).…”

Section: Formation Of C 16 -And C 24 -Ceramide Species Is Differentiamentioning

confidence: 99%

BcR-induced Apoptosis Involves Differential Regulation of C16 and C24-Ceramide Formation and Sphingolipid-dependent Activation of the Proteasome

Kroesen

Jacobs

Pettus

et al. 2003

Journal of Biological Chemistry

104

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In this study, we describe an ordered formation of long-and very long-chain ceramide species in relation to the progression of B-cell receptor (BcR) triggering induced apoptosis. An early and caspase-independent increase in long-chain ceramide species, in which C 16 -ceramide predominated, was observed 6 h after BcR triggering. In contrast, very long-chain ceramide species were generated later, 12-24 h after BcR triggering. The formation of these very long-chain ceramide species, in which C 24 -ceramide predominated, required the activation of effector caspases. BcR-induced formation of long-chain ceramide species resulted in proteasomal activation and degradation of XIAP and subsequent activation of effector caspases, demonstrating an important cell-biological mechanism through which longchain ceramides may be involved in the progression of BcR triggering induced apoptosis and subsequent formation of very long-chain ceramide species. BcR-induced activation of the proteasome was blocked with ISP-1/myriocin, a potent and selective inhibitor of serine palmitoyl transferase that catalyzes the first and rate-limiting step in the de novo formation of ceramide. Both ISP-1 and clasto-lactacystin ␤-lactone, an irreversible inhibitor of the proteasome, prevented BcR crosslinking-induced XIAP degradation. Also, a mutant XIAP lacking the ubiquitin-ligating ring finger motif was completely resistant to proteasome-mediated degradation, and Ramos cells overexpressing XIAP became highly resistant to BcR cross-linking-induced activation of caspases. The formation of C 16 -ceramide in response to BcR cross-linking was found unaltered in XIAP overexpressing Ramos cells, whereas C 24 -ceramide formation was completely abolished. These results demonstrate how de novo generated long-chain ceramide species may be involved in the activation of downstream effector caspases and subsequent formation of very long-chain ceramide species. As such, these results provide novel and important insights into the significance of specific ceramide species in defined stages of apoptosis.

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Mitochondria and ceramide: intertwined roles in regulation of apoptosis

Cited by 140 publications

References 108 publications

Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

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

BcR-induced Apoptosis Involves Differential Regulation of C16 and C24-Ceramide Formation and Sphingolipid-dependent Activation of the Proteasome

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