Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models.
We have previously reported that, in prostate cancer, inhibition of the oncogenic sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway is a key element in chemotherapy-induced apoptosis. Here, we show that selective pharmacologic inhibition of SphK1 triggers apoptosis in LNCaP and PC-3 prostate cancer cells, an effect that is reversed by SphK1 enforced expression. More importantly, we show for the first time that the up-regulation of the SphK1/S1P pathway plays a crucial role in the resistance of prostate cancer cells to chemotherapy. Importantly, pharmacologic SphK1 inhibition with the B-5354c compound sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to S1P sphingolipid ratio. To conclude, our study highlights the notion that drugs specifically designed to inhibit SphK1 could provide a means of enhancing the effects of conventional treatment through the prosurvival antiapoptotic SphK1/S1P pathway.
Pchejetski
Dimitri
D
Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, UMR 5089, 31077 Toulouse Cedex 4, France.
Doumerc
Nicolas
N
Golzio
Muriel
M
Naymark
Maria
M
Teissié
Justin
J
Kohama
Takafumi
T
Waxman
Jonathan
J
Malavaud
Bernard
B
Cuvillier
Olivier
O
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D004359:Drug Therapy, Combination; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D062366:para-Aminobenzoates; D000099157:Sphingosine Kinase
D010129:4-Aminobenzoic Acid; D000970:Antineoplastic Agents; D002166:Camptothecin; D020169:Caspases; D002518:Ceramides; D049452:Green Fluorescent Proteins; D000077146:Irinotecan; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D062366:para-Aminobenzoates; D000099157:Sphingosine Kinase; C416812:B 5354c; C060506:sphingosine 1-phosphate