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Sphingosine Kinase-1 as a Chemotherapy Sensor in Prostate Adenocarcinoma Cell and Mouse Models

¹ Inserm, U466, Toulouse, France; ² CNRS, Institut de Pharmacologie et de Biologie Structurale, UMR 5089, Toulouse, France; ³ Université Paul Sabatier, Faculté de Médecine, Hpital Rangueil, Service d'Urologie et de Transplantation Rénale, Toulouse, France; and ⁴ Université Paul Sabatier, Faculté de Médecine, Hpital Rangueil, Service d'Anatomie et Cytologie Pathologiques, Toulouse, France

Requests for reprints: Olivier Cuvillier, Institut National de la Santé et de la Recherche Médicale U466, BP 84225, 31432 Toulouse, France. Phone: 33-5-61-32-20-60; Fax: 33-5-61-32-20-84; E-mail: olivier.cuvillier{at}toulouse.inserm.fr.

Systemic chemotherapy was considered of modest efficacy in prostate cancer until the recent introduction of taxanes. We took advantage of the known differential effect of camptothecin and docetaxel on human PC-3 and LNCaP prostate cancer cells to determine their effect on sphingosine kinase-1 (SphK1) activity and subsequent ceramide/sphingosine 1-phosphate (S1P) balance in relation with cell survival. In vitro, docetaxel and camptothecin induced strong inhibition of SphK1 and elevation of the ceramide/S1P ratio only in cell lines sensitive to these drugs. SphK1 overexpression in both cell lines impaired the efficacy of chemotherapy by decreasing the ceramide/S1P ratio. Alternatively, silencing SphK1 by RNA interference or pharmacologic inhibition induced apoptosis coupled with ceramide elevation and loss of S1P. The differential effect of both chemotherapeutics was confirmed in an orthotopic PC-3/green fluorescent protein model established in nude mice. Docetaxel induced a stronger SphK1 inhibition and ceramide/S1P ratio elevation than camptothecin. This was accompanied by a smaller tumor volume and the reduced occurrence and number of metastases. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to docetaxel treatment. These results provide the first in vivo demonstration of SphK1 as a sensor of chemotherapy. (Cancer Res 2005; 65(24): 11667-75)

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