CB2 Cannabinoid Receptor-mediated Regulation of Prostate Cancer Growth

摘要： 前列腺癌是一个主要的健康问题，也是全球男性死亡的重要原因。家族史和种族是该病的两大危险因素。与高加索美国人或其他种族相比，非洲裔美国人的前列腺癌年龄调整发病率和死亡率明显更高。 在美国和全球范围内。因此，了解前列腺癌发生和发展的分子机制对于开发更有效的治疗策略是极其重要的。 大麻素(包括内源性大麻素)调节细胞死亡或细胞生长，这取决于大麻素的细胞类型和浓度。大麻素可以抑制前列腺癌细胞的生长。我们发现，大麻素受体-2(CB2)的激活抑制雄激素敏感型前列腺癌(AS PC)细胞的增殖和运动。我们的初步数据还表明，大麻类化合物具有选择性疗效，与LNCaP前列腺癌细胞相比，对正常前列腺上皮细胞产生的不良影响较小。尽管CB2受体在包括前列腺癌在内的许多肿瘤组织中都有高表达，但迄今为止，大多数大麻素的抗肿瘤作用都与CBI受体相关，而不是CB2受体的激活。体内条件下大麻素抗肿瘤作用的下游机制 人们对此了解甚少。此外，CB1受体在神经细胞和脑组织中高度表达。 因此，与CB2受体的激活不同，CB1受体的激活会产生神经行为和精神副作用。因此，CB2受体介导的前列腺癌治疗干预具有临床优势。 根据我们的初步数据，我们假设CB2受体的激活抑制雄激素敏感型前列腺癌(AS PC)的生长。为了验证这一假说，我们制定了以下两个具体目标：(1)确定CB2受体激活对培养的LNCaP和LAPC4前列腺癌细胞增殖、存活和迁移的影响，这与RhoA和粘着斑激酶(FAK)信号通路的激活有关；(2)确定外源性CB2受体激活和内源性大麻素活性增加对小鼠前列腺癌生长的影响与FAK活性有关。

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.