Wang Dingzhi, Wang Haibin, Ning Wei, Backlund Michael G, Dey Sudhansu K, DuBois Raymond N
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tenessee, USA.
Cancer Res. 2008 Aug 1;68(15):6468-76. doi: 10.1158/0008-5472.CAN-08-0896.
Although endocannabinoid signaling is important for certain aspects of gastrointestinal homeostasis, the role of the cannabinoid receptors (CB) in colorectal cancer has not been defined. Here we show that CB1 expression was silenced in human colorectal cancer due to methylation of the CB1 promoter. Our genetic and pharmacologic studies reveal that loss or inhibition of CB1 accelerated intestinal adenoma growth in Apc(Min/+) mice whereas activation of CB1 attenuated intestinal tumor growth by inducing cell death via down-regulation of the antiapoptotic factor survivin. This down-regulation of survivin by CB1 is mediated by a cyclic AMP-dependent protein kinase A signaling pathway. These results indicate that the endogenous cannabinoid system may represent a potential therapeutic target for prevention or treatment of colorectal cancer.
尽管内源性大麻素信号传导对胃肠道稳态的某些方面很重要，但大麻素受体（CB）在结直肠癌中的作用尚未明确。在此我们表明，由于CB1启动子的甲基化，CB1在人类结直肠癌中表达沉默。我们的遗传学和药理学研究表明，CB1的缺失或抑制加速了Apc(Min/+)小鼠肠道腺瘤的生长，而CB1的激活通过下调抗凋亡因子存活素诱导细胞死亡，从而减弱肠道肿瘤生长。CB1对存活素的这种下调是由环磷酸腺苷依赖性蛋白激酶A信号通路介导的。这些结果表明，内源性大麻素系统可能是预防或治疗结直肠癌的潜在治疗靶点。
