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Loss Of Cannabinoid Receptor 1 Accelerates Intestinal Tumor Growth

Julie Gardener

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Loss of cannabinoid receptor 1 accelerates intestinal tumor growth​
Dingzhi Wang, Haibin Wang, Wei Ning, Michael G. Backlund, Sudhansu K. Dey, and Raymond N. DuBois
Cancer Res. 2008 August-available in PMC 2009 August


Abstract

Although endocannabinoid signaling is important for certain aspects of gastrointestinal homoeostasis, 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 ApcMin/+ mice whereas activation of CB1 attenuated intestinal tumor growth by inducing cell death via downregulation of the anti-apoptotic factor survivin. This downregulation of survivin by CB1 is mediated by a cAMP-dependent PKA signaling pathway. These results indicate that the endogenous cannabinoid system may represent a potential therapeutic target for prevention or treatment of colorectal cancer.

Introduction
Cannabinoids are currently used to treat chemotherapy- or radiotherapy-induced nausea, vomiting as well as for pain relief, insomnia relief, mood elevation, and appetite stimulation. Medicinal use of these compounds is also thought to be beneficial for digestive disorders such as diarrhea and Crohn’s disease. Plant-derived cannabinoids and their derivatives exert a wide variety of biological effects by mimicking endogenous compounds (endocannabinoids), which primarily activate two cannabinoid-specific G-protein-coupled receptors, CB1 and CB2, encoded by the Cnr1 and Cnr2 genes, respectively. Studies have recently suggested that cannabinoids exert potential anti-tumor effects on a wide spectrum of human tumor cell lines in culture and in xenograft studies and have anti-inflammatory properties. CB1 and CB2 can activate several different cellular pathways depending on the biologic context being examined. However, there is currently no in vivo genetic evidence demonstrating the role of the endocannabinoid system in mouse models of cancer.
The gastrointestinal tract of mice, rats and humans produce two major endocannabinoids, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG). Interestingly, human colorectal cancers (CRCs) and adenomas produce two to three times more AEA and 2-AG than does the neighboring normal mucosa. In humans and mice, CB1 is expressed in normal colonic epithelium, smooth muscle, and the submucosal myenteric plexus. CB2 is found mainly in subepithelial macrophages of normal colonic tissues. However, little is known regarding the expression of cannabinoid receptors in CRC.
Endocannabinoid signaling is important in regulating gastrointestinal motility, secretion, and neurotransmitter release. For example, the endocannabinoid signaling has been implicated in an autoimmune intestinal disorder; specifically, Cnr1−/− mice exhibited a stronger inflammatory response in the colon than did wild-type mice in response to treatment with pro-inflammatory agents, suggesting that CB1 provides intrinsic protection against colonic inflammation. Since chronic inflammation is a known risk factor for CRC, the aim of the present study was to determine the role of cannabinoid receptors in a mouse model of colon cancer and the mechanism of the receptor action.

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