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: Giuditta Illuzzi, Caterina Bernacchioni, Massimo Aureli, Simona Prioni, Gianluca Frera, Chiara Donati, Manuela Valsecchi, Vanna Chigorno, Paola Bruni, Sandro Sonnino, Alessandro Prinetti
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 24 Pg. 18594-602 (Jun 11 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20404323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Lipids
• RNA, Messenger
• Fenretinide
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase

Topics

• Antineoplastic Agents (pharmacology)
• Cell Death
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Drug Resistance, Neoplasm
• Female
• Fenretinide (pharmacology)
• Humans
• Lipids (chemistry)
• Mass Spectrometry (methods)
• Models, Biological
• Ovarian Neoplasms (drug therapy)
• Phosphotransferases (Alcohol Group Acceptor) (metabolism)
• RNA, Messenger (metabolism)