title: Sphingosine kinase mediates resistance to the synthetic retinoid N-(4-hydroxyphenyl)retinamide in human ovarian cancer cells.
abstract: 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.
authors.affiliation: Department of Medical Chemistry, University of Milan, Center of Excellence on Neurodegenerative Diseases, 20090 Segrate, Italy.
authors.forename: Giuditta
authors.initials: G
authors.lastname: Illuzzi
authors.forename: Caterina
authors.initials: C
authors.lastname: Bernacchioni
authors.forename: Massimo
authors.initials: M
authors.lastname: Aureli
authors.forename: Simona
authors.initials: S
authors.lastname: Prioni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Frera
authors.forename: Chiara
authors.initials: C
authors.lastname: Donati
authors.forename: Manuela
authors.initials: M
authors.lastname: Valsecchi
authors.forename: Vanna
authors.initials: V
authors.lastname: Chigorno
authors.forename: Paola
authors.initials: P
authors.lastname: Bruni
authors.forename: Sandro
authors.initials: S
authors.lastname: Sonnino
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prinetti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D017313:Fenretinide; D008055:Lipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D000099157:Sphingosine Kinase
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