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

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Abstract
1 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. 2 Reverse transcription (RT)–polymerase chain reaction (PCR) analysis demonstrated that HT‐29 cells are endowed with the naïve expression of CCK‐2 receptor (short splice variant), COX‐1, COX‐2 and prostaglandin EP4 receptor, but not gastrin. 3 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 (EP4 receptor antagonist) partly reversed gastrin‐17‐induced cell growth, while they fully antagonized the enhancing action on DNA synthesis. 4 HT‐29 cells responded to gastrin‐17 with a significant increase in prostaglandin E2 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. 5 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 E2 release was prevented by PD98059 or wortmannin. 6 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 E2 production and EP4 receptor activation; (c) the recruitment of COX‐2/prostaglandin pathways contributes to the growth‐promoting actions exerted by gastrin‐17. British Journal of Pharmacology (2005) 144, 338–348. doi:10.1038/sj.bjp.0706053