Deregulation of cell survival pathways and resistance to apoptosis are widely accepted to be fundamental aspects of tumorigenesis. As in many tumours, the aberrant growth and survival of colorectall tumour cells is dependent upon a small number of highly activated signalling pathways, the inhibition of which elicits potent growth inhibitory or apoptotic responses in tumour cells. Accordingly, there is considerable interest in therapeutics that can modulate survival signalling pathways and target cancer cells for death. There is emerging evidence that cannabinoids, especially Delta(9)-tetra-hydrocannabinol (THC), may represent novel anticancer agents, due to their ability to regulate signalling pathways critical for cell growth and survival. Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectall cancer cells. THC-induced apoptosis was rescued by pharmacological blockade of the CB1, but not CB2, can- nabinoid receptor. Importantly, THC treatment resulted in CB1-mediated inhibition of both RAS-MAPK/ERK and PI3K-AKT survival signalling cascades; two key cell survival pathways frequently deregulated in colorectal tumours. The inhibition of ERK and AT activity by THC was accompanied by activation of the proapoptotic BCL-2 family member BAD. Reduction of BAD protein expression by RNA interference rescued colorectal cancer cells from THC-induced apoptosis. These data suggest an important role for CB I receptors and BAD in the regulation of apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy. (c) 2007 Wiley-Liss, Inc.
