Send to

Choose Destination
Br J Pharmacol. 2005 Feb;144(3):338-48.

Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E2 production.

Author information

Interdepartmental Center for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Via Roma 55, 56126 Pisa, Italy.


The present study investigates the effects of gastrin-17 on human colon cancer HT-29 cells to examine whether gastrin receptor (CCK-2), cyclooxygenase (COX-1, COX-2) isoforms and prostaglandin receptor pathways interact to control cell growth. Reverse transcription (RT)-polymerase chain reaction (PCR) analysis demonstrated that HT-29 cells are endowed with the naive expression of CCK-2 receptor (short splice variant), COX-1, COX-2 and prostaglandin EP(4) receptor, but not gastrin. Gastrin-17 significantly promoted cell growth and DNA synthesis. Both these stimulating effects were abolished by L-365,260 or GV150013 (CCK-2 receptor antagonists), but were unaffected by SC-560 (COX-1 inhibitor). L-745,337 (COX-2 inhibitor) or AH-23848B (EP(4) receptor antagonist) partly reversed gastrin-17-induced cell growth, while they fully antagonized the enhancing action on DNA synthesis. HT-29 cells responded to gastrin-17 with a significant increase in prostaglandin E(2) release. This enhancing effect was completely counteracted by L-365,260, GV150013 or L-745,337, while it was insensitive to cell incubation with SC-560. Exposure of HT-29 cells to gastrin-17 was followed by an increased phosphorylation of both extracellular regulated kinases (ERK-1/ERK-2) and Akt. Moreover, gastrin-17 enhanced the transcriptional activity of COX-2 gene promoter and stimulated COX-2 expression. These latter effects were antagonized by L-365,260 or GV150013, and could be blocked also by PD98059 (inhibitor of ERK-1/ERK-2 phosphorylation) or wortmannin (inhibitor of phosphatidylinositol 3-kinase). Analogously, gastrin-17-induced prostaglandin E(2) release was prevented by PD98059 or wortmannin. The present results suggest that (a) in human colon cancer cells endowed with CCK-2 receptors, gastrin-17 is able to enhance the transcriptional activity of COX-2 gene through the activation of ERK-1/ERK-2- and phosphatidylinositol 3-kinase/Akt-dependent pathways; (b) these stimulant actions lead to downstream increments of COX-2 expression, followed by prostaglandin E(2) production and EP(4) receptor activation; (c) the recruitment of COX-2/prostaglandin pathways contributes to the growth-promoting actions exerted by gastrin-17.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center