The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells

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 colorectal 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 D9
-tetrahydrocannabinol (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 colorectal cancer cells. THC-induced apoptosis was rescued by pharmacological blockade of the CB1, but not CB2, cannabinoid 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 AKT 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 CB1 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.