Spisulosine (ES-285) Induces Prostate Tumor PC-3 and LNCaP Cell Death by De Novo Synthesis of Ceramide and PKCzeta Activation

During the past decades, intense attention has been focused on the anti-tumor properties of marine compounds which some of them have been revealed as potent apoptotic inducers. In the present work, we studied the mechanism of action of a new compound, Spisulosine (ES-285), isolated from the sea mollusc Spisula polynyma, in the prostate tumor PC-3 and LNCaP cell lines. Spisulosine inhibited cell proliferation with an IC50 of 1 microM in both cell lines, although it was more effective in the androgen-independent PC-3 cells. The anti-proliferative effect induced by Spisulosine in prostate cells was independent of peroxisome proliferator activated receptor gamma (PPARgamma) and phosphatidylinositol 3-kinase/(PI3K/Akt), Jun N-terminal kinase (JNK), p38 or classical protein kinase C (PKCs) pathways, as it was inferred from the results obtained with specific inhibitors of these routes. However, Spisulosine treatment of prostate cells induced an increase in the intracellular ceramide levels, that was totally blocked by the ceramide synthase inhibitor Fumonisin B1, indicating that the ceramide accumulation came from the de novo biosynthesis. Spisulosine also induced in both PC-3 and LNCaP cells, an activation of the atypical PKC isoform, PKCzeta, which is one of the target proteins of ceramide. These results indicate that the marine compound Spisulosine inhibits the growth of the prostate PC-3 and LNCaP cells through intracellular ceramide accumulation and PKCzeta activation.