CB2 Cannabinoid Receptor-mediated Regulation of Prostate Cancer Growth

CB2 大麻素受体介导的前列腺癌生长调节

• 批准号: 8068504
• 负责人: Keith Burridge
• 金额: $ 1.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068504
• 关键词: Adverse effects; African American; Age; Androgen Receptor; Androgens; CNR1 gene; Cancer Patient; Cancerous; Cannabinoids; Cell Death; Cell Proliferation; Cells; Clinical; Data; Development; Disease; Endocannabinoids; Epithelial Cells; Ethers; Family history of; Focal Adhesion Kinase 1; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Hormones; Immigration; Incidence; LAPC4; LNCaP; Link; Malignant neoplasm of prostate; Mediating; Molecular; Monomeric GTP-Binding Proteins; Mus; Neurons; Pathway interactions; Prostate; Prostatic Neoplasms; Race; Receptor Activation; Regulation; Resistance; Risk Factors; Signal Pathway; Signal Transduction; Stream; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Tumor Tissue; Xenograft Model; abstracting; anticancer activity; base; brain tissue; cancer cell; cancer therapy; cannabinoid receptor; caucasian American; cell growth; cell motility; cell type; desensitization; hormone therapy; human tissue; in vivo; men; mortality; neurobehavioral; novel; novel therapeutics; potency testing; receptor; receptor expression; rho; tumor; tumor growth

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 worldwide. 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 growth 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 normal prostate epithelial cells compared to LNCaP prostate cancer cells. To date most of the anti-tumor effects of cannabinoids have been correlated with the CB1 receptors rather than CB2 receptor activation, although CB2 receptor expression is high in many tumor tissues including prostate tumor. However downstream mechanisms mediaflng anti-tumor effects of cannabinoids under/f7 wVo conditions are poorly understood. Further, CBI receptors are highly expressed in neuronal cells and brain tissue. Therefore, unlike activation of CB2 receptors, CBI receptor activation produces neurobehavioral and psychotropic side effects. Thus, CB2 receptor-mediated therapeutic intervenflon 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) growth. 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 migratlon in relation to activatlon of RhoA and the focal adhesion kinase (FAK) signaling pathway; and (2) To determine the effects of exogenous activation of CB2 receptor and increase in endogenous cannabinoid activity on AS prostate cancer growrth in mice in relation to FAK activity.

摘要： 前列腺癌是一个主要的健康问题，也是世界范围内男性死亡的重要原因。家族史和种族是这种疾病的两个主要危险因素。与白种人或其他种族相比，非裔美国人的前列腺癌年龄校正发病率和死亡率明显较高 在美国和世界各地。因此，了解负责前列腺癌的发展和进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。大麻素抑制前列腺癌细胞的生长。我们已经发现大麻素受体-2（CB 2）的激活抑制雄激素敏感性前列腺癌（AS PC）细胞增殖和运动。我们的初步数据还表明，大麻素化合物具有选择性功效，与LNCaP前列腺癌细胞相比，对正常前列腺上皮细胞产生较少的不良影响。迄今为止，大麻素的大多数抗肿瘤作用与CB 1受体而不是CB 2受体活化相关，尽管CB 2受体在包括前列腺肿瘤在内的许多肿瘤组织中表达很高。然而，下游机制介导了大麻素在体外条件下的抗肿瘤作用。 我们对此知之甚少。此外，CBI受体在神经元细胞和脑组织中高度表达。 因此，与CB 2受体的活化不同，CBI受体活化产生神经行为和精神方面的副作用。因此，CB 2受体介导的前列腺癌治疗性干预具有临床优势。 基于我们的初步数据，我们假设CB 2受体的激活抑制雄激素敏感性前列腺癌（AS PC）的生长。为了验证这一假设，我们开展了以下两个具体的目标：（1）确定CB 2受体激活对培养的LNCaP和LAPC 4前列腺癌细胞增殖、存活和迁移的影响与RhoA和粘着斑激酶（FAK）信号通路的激活的关系;（2）探讨外源性激活CB_2受体和提高内源性大麻素活性对小鼠AS前列腺癌生长的影响及其与FAK活性的关系。