The cannabinoid R+ methanandamide induces IL-6 secretion by prostate cancer PC3 cells

In the present study, we have investigated the effect of the cannabinoid R+ methanandamide (MET) in the androgen-resistant prostate cancer PC3 cells. MET induced a dose-dependent decrease in PC3 cell viability as well as a dose-dependent increase in the secretion of the cytokine IL-6. Looking deeper into the mechanisms involved, we found that MET-induced de novo synthesis of the lipid mediator ceramide that was blocked by the ceramide synthase inhibitor Fumonisin B1. Pre-incubation of cells with the cannabinoid receptor CB2 antagonist SR 144528 (SR2), but not the CB1 antagonist Rimonabant or the TRPV1 antagonist capsazepine, partially prevented the anti-proliferative effect, the ceramide accumulation, and the IL-6-induced secretion, suggesting a CB2 receptor-dependent mechanism. Fumonisin B1 did not have any effect in the IL-6 secretion increase induced by MET. However, even an incomplete down-regulation of (i.e., not a total silencing of) ceramide kinase expression by specific siRNA prevented the MET-induced IL-6 secretion. These results suggest that MET regulates ceramide metabolism in prostate PC3 cells which is involved in cell death as well as in IL-6 secretion. Our findings also suggest that CB2 agonists may offer a novel approach in the treatment of prostate cancer by decreasing cancer epithelial cell proliferation. However, the interaction of prostate cancer cells with their surrounding, and in particular with the immune system in vivo, needs to be further explored.