Turned-off cannabinoid receptor turns on colorectal tu...(ndocannabinoid signaling is important to...),Health

Date:7/31/2008

ndocannabinoid signaling is important to the normal functioning of the digestive system and has been shown to protect the colon against inflammation. Since chronic inflammation is a known risk factor for colorectal cancer, the researchers decided to look into the role of cannabinoid receptors in a mouse model of colon cancer.

"People have looked at cannabinoids in cancer earlier, mainly in cell culture experiments," DuBois said. "The molecular mechanisms for loss of the receptor and its effect on cancer have not been previously shown."

First, the team found that CB1 was largely absent in 18 of 19 human tumor specimens and in 9 of 10 colorectal cancer cell lines. Further experimentation showed that the gene that encodes the CB1 protein was not damaged, but shut down chemically by the attachment of methyl groups - a carbon atom surrounded by three hydrogen atoms - to the gene encoding CB1.

Treating cell lines with decitabine, a demethylating agent approved for some types of leukemia, removed the methyl groups, restoring gene expression in 7 of 8 cell lines and full expression of CB1 protein in three lines.

Next, the group found that deletion of the CB1 gene in a strain of mice that spontaneously develops precancerous polyps resulted in a 2.5-to-3.8-fold increase in the number of polyps and a 10-fold increase in the number of large growths, those most likely to develop into cancer.

Treating mice that had the CB1 receptor with an endocannabinoid agonist resulted in a decline in polyps ranging from 16.7 percent to 50 percent. The reduction was greater for larger polyps.

CB1 thwarts survivin, a protein that protects cancer

Cannabinoids previously had been shown to kill cancer cells in lab experiments by inducing apoptosis - programmed cell death. The team confirmed the role of CB1 in apoptosis, showing that tumor cells with high CB1 expression were sensitive to apoptosis when treated by a cannabinoid
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Contact: Scott Merville smerville@mdanderson.org 713-792-0661 University of Texas M. D. Anderson Cancer Center Source:Eurekalert

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