Involvement of Dihydroceramide Desaturase in Cell Cycle Progression in Human Neuroblastoma Cells

Kraveka, Jacqueline M.; Li, Li; Szulc, Zdzisław M.; Bielawski, Jacek; Öğretmen, Besim; Hannun, Yusuf A.; Obeid, Lina M.; Bielawska, Alicja

doi:10.1074/jbc.m700647200

Cited by 163 publications

(191 citation statements)

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“…1, a number of enzymes participate in the salvage pathway, and these include members of the LASS family, acid SMase, and acid ceramidase. The relatively recent development of RNAi [66] has allowed the selective knock-down of these genes individually [23,[67][68][69][70]. The implication of several of the above genes along the pathway of ceramide formation provides strong evidence for the operation of this pathway.…”

Section: Iii) An Increase In Free Sphingosinementioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

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457

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Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. Of these, ceramide is a central metabolite and plays key roles in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Ceramide is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups. Sphingosine serves as the product of sphingolipid catabolism, and it is mostly salvaged through re-acylation, resulting in the generation of ceramide or its derivatives. This recycling of sphingosine is termed the "salvage pathway", and recent evidence points to important roles for this pathway in ceramide metabolism and function. A number of enzymes are involved in the salvage pathway, and these include sphingomyelinases, cerebrosidases, ceramidases, and ceramide synthases. Recent studies suggest that the salvage pathway is not only subject to regulation, but it also modulates the formation of ceramide and subsequent ceramide-dependent cellular signals. This review focuses on the salvage pathway in ceramide metabolism, its regulation, its experimental analysis, and emerging biological functions.

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Section: Iii) An Increase In Free Sphingosinementioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

Self Cite

540

457

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“…It has also been shown that the combined use of lactoferricin and tamoxifen, due to its known inhibitory effect on GCS function, enhances the apoptotic effects of lactoferricin, and thus, it leads to increased levels of apoptosis in Jurkat T cell leukemia cells [79]. The imino sugar OGT2378 that is also an inhibitor of GCS reduced the tumorigenic capability of MEB4 melanoma cells [80]. It has been shown that GCS is overexpressed in many multidrug-resistant cancer cell lines in leukemia, breast cancer, and renal cell cancer [64].…”

Section: Glucosylceramide Synthase In Cancer Therapymentioning

confidence: 99%

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Yandım

Apohan

Baran

2012

Cancer Chemother Pharmacol

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Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDPglucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

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“…HPR-induced production of ceramide mainly occurs via de novo synthesis, because HPR activates both serine palmitoyltransferase and dihydroceramide synthase (20,21) that catalyze the first steps in sphingolipid biosynthesis (22). Moreover, it has been recently shown that HPR concomitantly inhibits dihydroceramide desaturase (22,23), suggesting that dihydroceramide rather than (or in addition to) ceramide might mediate HPRinduced toxicity (24) possibly involving other mechanisms of death in addition to apoptosis. In this work, we investigate whether the resistance to HPR of human ovarian cancer cells could be associated with the activation of the SK/S1P leading to an altered dihydroceramide/S1P ratio that could prevent or overcome ceramide-mediated HPR-induced cell death.…”

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Sphingosine Kinase Mediates Resistance to the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide in Human Ovarian Cancer Cells

Illuzzi

Bernacchioni

Aureli

et al. 2010

Journal of Biological Chemistry

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A2780 human ovarian carcinoma cells respond to treatment with the synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) with the production of dihydroceramide and with a concomitant reduction of cell proliferation and induction of apoptosis. The derived HPR-resistant clonal cell line, A2780/HPR, is less responsive to HPR in terms of dihydroceramide generation. In this report, we show that the production of sphingosine 1-phosphate (S1P) is significantly higher in A2780/HPR versus A2780 cells due to an increased sphingosine kinase (SK) activity and SK-1 mRNA and protein levels. Treatment of A2780 and A2780/HPR cells with a potent and highly selective pharmacological SK inhibitor effectively reduced S1P production and resulted in a marked reduction of cell proliferation. Moreover, A2780/HPR cells treated with a SK inhibitor were sensitized to the cytotoxic effect of HPR, due to an increased dihydroceramide production. On the other hand, the ectopic expression of SK-1 in A2780 cells was sufficient to induce HPR resistance in these cells. Challenge of A2780 and A2780/HPR cells with agonists and antagonists of S1P receptors had no effects on their sensitivity to the drug, suggesting that the role of SK in HPR resistance in these cells is not mediated by the S1P receptors.These data clearly demonstrate a role for SK in determining resistance to HPR in ovarian carcinoma cells, due to its effect in the regulation of intracellular ceramide/S1P ratio, which is critical in the control of cell death and proliferation.Ovarian cancer is the fifth most common cancer, and it is the leading cause of death from all types of gynecological cancer. This carcinoma has a high rate of recurrence and subsequent mortality after chemotherapy; many patients relapse after first line treatment, and only the 15% are long survivors. The failure of this kind of treatment is generally caused by the acquisition of drug resistance. Cancer cells develop multiple mechanisms to evade drug toxicity. Several commonly used anticancer drugs, including daunorubicin, vincristine, and retinoids, exert their cytotoxic action at least in part by triggering the production of the sphingolipid ceramide, a mediator of apoptosis and an inhibitor of cell proliferation in a variety of tumor cell lines (1). It has been demonstrated that chemoresistant tumor and tumor cell lines are frequently characterized by the increased glycosylation of ceramide with formation of glucosylceramide, due to an increased expression or activation of glucosylceramide synthase (2). Scavenging ceramide via its increased glycosylation would allow tumor cells to escape ceramide-induced apoptosis, thus contributing to the drug-resistant phenotype (3-5). However, it has been shown that GlcCer accumulation is not the only consequence of an altered sphingolipid metabolism in drug-resistant cancer cells. In multidrugresistant human ovarian carcinoma cells, sphingomyelin and galactosylceramide levels were also higher respect to parental sensitive cells, whereas lactosylceramide and all more compl...

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Involvement of Dihydroceramide Desaturase in Cell Cycle Progression in Human Neuroblastoma Cells

Cited by 163 publications

References 43 publications

The sphingolipid salvage pathway in ceramide metabolism and signaling

The sphingolipid salvage pathway in ceramide metabolism and signaling

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Sphingosine Kinase Mediates Resistance to the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide in Human Ovarian Cancer Cells

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