Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism

Mengubas, K; Riordan, FA; Bravery, CA; Lewin, Jackie; Dl, Owens; Mehta, AB; Av, Hoffbrand; Wickremasinghe, RG

doi:10.1038/sj.onc.1202622

Cited by 38 publications

(35 citation statements)

References 41 publications

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“…Ceramide, which can be generated through either de novo synthesis or via acid hydrolysis of sphingomyelin (73), has been established as an inducer of apoptosis in neoplastic cells, including those of hematopoietic origin (43). In this regard, induction of apoptosis in leukemic cells by ara-C has been associated with increased ceramide levels (42), and of particular relevance to the present studies, ceramide generation has been implicated in the lethal actions of F-ara-AMP in B-chronic lymphocytic leukemia cells (44,74). Furthermore, it has been shown that perturbations in ceramide metabolism can enhance the sensitivity of tumor cells to conventional cytotoxic drugs (75).…”

Section: Discussionmentioning

confidence: 87%

The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells

et al. 2004

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Interactions between the novel benzamide histone deacetylase (HDAC) inhibitor MS-275 and fludarabine were examined in lymphoid and myeloid human leukemia cells in relation to mitochondrial injury, signal transduction events, and apoptosis. Prior exposure of Jurkat lymphoblastic leukemia cells to a marginally toxic concentration of MS-275 (e.g., 500 nM) for 24 h sharply increased mitochondrial injury, caspase activation, and apoptosis in response to a minimally toxic concentration of fludarabine (500 nM), resulting in highly synergistic antileukemic interactions and loss of clonogenic survival. Simultaneous exposure to MS-275 and fludarabine also led to synergistic effects, but these were not as pronounced as observed with sequential treatment. Similar interactions were noted in the case of (a)

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Section: Discussionmentioning

confidence: 87%

The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells

et al. 2004

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“…It was recently reported that the killing of Jurkat cells by synthetic ceramide could occur by both apoptotic and non-apoptotic mechanisms (Mengubas et al, 1999a(Mengubas et al, , 1999b. In those studies, zVAD-fmk did not decrease the overall rate of killing of Jurkat cells by C2-ceramide, but did dramatically decrease the induction of apoptosis.…”

Section: C2-ceramide Induces Dna Fragmentation That Is Caspase-dependmentioning

confidence: 87%

Ceramide Induces Cell Death in the Human Prostatic Carcinoma Cell Lines PC3 and DU145 but Does Not Seem to Be Involved in Fas-Mediated Apoptosis

Gewies

Rokhlin

Cohen

2000

Laboratory Investigation

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SUMMARY:Treatment of cells with synthetic C2-ceramide has been reported to induce apoptosis in several cell systems, and endogenously formed ceramide has been proposed to act as a second messenger, activating signaling pathways which contribute to the execution of apoptotic cell death after Fas ligation or tumor necrosis factor receptor-1 ligation. In this study, we examined the effect of exogenously administered C2-ceramide on the human prostatic carcinoma cell lines PC3 (Fas-sensitive) and DU145 (Fas-resistant). In both cell lines, C2-ceramide induced cell death in a dose-dependent manner, whereas a structural analog, C2-dihydroceramide, did not. The pan-caspase inhibitor zVAD-fmk did not prevent C2-ceramide-induced cell death but did prevent C2-ceramide-induced DNA fragmentation, indicating that apoptotic and non-apoptotic mechanisms are involved in C2-ceramide-induced death. Interestingly, cycloheximide prevented C2-ceramide-induced DNA fragmentation, indicating that ceramide-induced apoptosis in PC3 and DU145 requires new protein synthesis. In addition, because cycloheximide converts Fas-resistant DU145 to Fas-sensitive as assessed by DNA fragmentation, ceramide does not seem to play a major role in the Fas-mediated pathway in this cell line. We also determined the levels of endogenous sphingomyelin after Fas ligation in PC3. No decrease of sphingomyelin levels could be detected after Fas activation. We conclude that sphingomyelinase-generated ceramide does not play a role in Fas-mediated apoptosis in PC3, and that there are fundamental differences in the mechanisms of cell death induced by C2-ceramide and Fas ligation. (Lab Invest 2000, 80:671-676).

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“…In particular, ceramide-mediated apoptotic cell death is extensively investigated (8 -10). On the other hand, several investigations indicate that nonapoptotic cell death is induced in certain tumor or normal cells by ceramide (11)(12)(13). However, the molecular pathways underlying the latter cell death remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells

et al. 2004

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The sphingolipid ceramide has been recognized as an important second messenger implicated in regulating diverse signaling pathways especially for apoptosis. Very little is known, however, about the molecular mechanisms underlying nonapoptotic cell death induced by ceramide. In the present study, we first demonstrate that ceramide induces nonapoptotic cell death in malignant glioma cells. The cell death was accompanied by several specific features characteristic of autophagy: presence of numerous autophagic vacuoles in the cytoplasm, development of the acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3), and a marked increase in expression levels of two forms of LC3 protein (LC3-I and LC3-II). We additionally demonstrate that ceramide decreases mitochondrial membrane potential and activates the transcription of death-inducing mitochondrial protein, BNIP3, resulting in increased expression levels of its mRNA and protein in malignant glioma cells. Moreover, tumor cells transfected with BNIP3 gene undergo autophagy in the absence of ceramide. These results suggest that ceramide induces autophagic cell death in malignant glioma cells via activation of BNIP3. This study adds a new concept to characterize the pathways by which ceramide acts to induce nonapoptotic autophagic cell death in malignant gliomas.

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Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism

Cited by 38 publications

References 41 publications

The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells

The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells

Ceramide Induces Cell Death in the Human Prostatic Carcinoma Cell Lines PC3 and DU145 but Does Not Seem to Be Involved in Fas-Mediated Apoptosis

Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells

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