First evidence of sphingosine 1-phosphate lyase protein expression and activity down-regulation in human neoplasm. Implication for resistance to therapeutics in prostate cancer
Menée sur des lignées cellulaires de cancer de la prostate, cette étude met en évidence le rôle joué par une enzyme, la sphingosine 1-phosphate lyase, dans la résistance thérapeutique
This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared to normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on tissue microarray, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In constrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance towards cell death. Interestingly, the S1P degradation products failed to sensitize to chemo- and radiotherapy supporting the crucial role of ceramide/S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating S1P lyase and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments.
http://mct.aacrjournals.org/content/early/2012/07/10/1535-7163.MCT-12-0227.abstract