Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models.
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.
Pchejetski
Dimitri
D
Inserm, U466, Toulouse, France.
Golzio
Muriel
M
Bonhoure
Elisabeth
E
Calvet
Cyril
C
Doumerc
Nicolas
N
Garcia
Virginie
V
Mazerolles
Catherine
C
Rischmann
Pascal
P
Teissié
Justin
J
Malavaud
Bernard
B
Cuvillier
Olivier
O
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology; D002518:Ceramides / Q000378:metabolism; D004195:Disease Models, Animal; D000077143:Docetaxel; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000099157:Sphingosine Kinase
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D002518:Ceramides; D000077143:Docetaxel; D049452:Green Fluorescent Proteins; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D043823:Taxoids; D000099157:Sphingosine Kinase; C485184:enhanced green fluorescent protein; C060506:sphingosine 1-phosphate