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Loss of Cannabinoid Receptor 1 Accelerates Intestinal Tumor Growth

Departments of ¹ Medicine, ² Pediatrics, ³ Cancer Biology, and ⁴ Cell and Developmental Biology, and ⁵ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tenessee; and ⁶ Departments of Gastrointestinal Oncology and Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Raymond N. DuBois, The University of Texas M. D. Anderson Cancer Center, Unit 118, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-4495; Fax: 713-745-4496; E-mail: rdubois{at}mdanderson.org.

Key Words: Colorectal cancer • Cannabinod receptors • Apoptosis • Survivin • and Methylation

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. [Cancer Res 2008;68(15):6468–76]