Carcinogenesis, Vol. 21, No. 10, 1789-1793,
October 2000
© 2000 Oxford University Press
Cancer Biology |
Cholinergic receptor up-regulates COX-2 expression and prostaglandin E2 production in colon cancer cells
Division of Oncologic Gastroenterology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
The M3 muscarinic cholinergic receptor has important physiological functions on normal colonic cells. It is frequently expressed on human colon cancer cells and is biologically active. Although it is mitogenic in certain cell models, the importance of this receptor on colon carcinogenesis is unknown. In the present study we have determined expression of the M3 receptor on human colon cancer tissue compared with matched normal tissue and examined the downstream effect of receptor activation in the HT-29 human colon carcinoma cell line. Using reverse transcription–PCR, M3 receptor RNA expression was detected in all matched colon carcinoma and normal specimens from eight patients. Five of the eight (62%) patients showed an up to 8-fold greater level of M3 receptor expression in cancer compared with the matched normal tissue. Exposure of HT-29 cells to carbachol, a stable receptor agonist, results in a 10-fold increase in cyclooxygenase-2 (COX-2) protein. This induction of COX-2 protein was dose dependent and was inhibited by the cholinergic receptor antagonist N-methylscopolamine (NMS). Carbachol caused a dose-dependent increase in prostaglandin E2 (PGE2), the main product of cyclooxygenase activity. The maximum stimulatory effect (40-fold increase) was noted with 1mM carbachol. The increase in PGE2 was completely abolished by NMS and by the COX-2 selective inhibitor NS398. This suggests that the M3 receptor mediates PGE2 production by a mechanism involving COX-2. As COX-2 and PGE2 are known promoters of gastrointestinal cancer, these data suggest that M3 receptor activation may facilitate progression of colon carcinoma, in part by a COX-2-mediated cellular mechanism.
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