CB2 Cannabinoid Receptor-mediated Regulation of Prostate Cancer Growth

文摘:

Abstract: Prostate cancer is a major health problem and a significant cause of mortality in men woridwide. Family history and race are the two major risk factors for this disease. The age-adjusted incidence rate and mortality rate of prostate cancer is significantly higher in African-Americans compared to Caucasian-Americans or other races in the US and woridwide. Thus, an understanding of the molecular mechanism responsible for the development and progression of prostate cancer is extremely important to the development of more effective therapeutic strategies. Cannabinoids (including endocannabinoids) regulate cell death or cell growth, depending on the cell type and concentration of the cannabinoid. Cannabinoids inhibit the growrth of prostate cancer cells. We have found that activation of cannabinoid receptor-2 (CB2) inhibits androgen-sensitive prostate cancer (AS PC) cell proliferation and motility. Our preliminary data also suggest that cannabinoid compounds possess selective efficacy, producing less adverse effects on nornial prostate epithelial cells compared to LNCaP prostate cancer cells. To date most of the anti-tumor effects of cannabinoids have been correlated with the CBI receptors rather than CB2 receptor activation, although CB2 receptor expression is high in many tumor tissues including prostate tumor. However downstream mechanisms mediating anti-tumor effects of cannabinoids under in vivo conditions are poorly understood. Further, CB1 receptors are highly expressed in neuronal cells and brain tissue. Therefore, unlike activation of CB2 receptors, CB1 receptor activation produces neurobehavioral and psychotropic side effects. Thus, CB2 receptor-mediated therapeutic intervention of prostate cancer has clinical advantages. Based on our preliminary data we hypothesize that activation of CB2 receptor inhibits androgen-sensitive prostate cancer (AS PC) growrth. To test this hypothesis, we have developed the following 2 specific aims: (1) To determine the effects of CB2 receptor activation on cultured LNCaP and LAPC4 prostate cancer cell proliferation, viability and migration in relation to activation of RhoA and the focal adhesion kinase (FAK) signaling pathway; and (2) To detemiine the effects of exogenous activation of CB2 receptor and increase in endogenous cannabinoid activity on AS prostate cancer growth in mice in relation to FAK activity.