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.