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Gastrin promotes human colon cancer cell growth via CCK‐2 receptor‐mediated cyclooxygenase‐2 induction and prostaglandin E 2 production
Author(s) -
Colucci Rocchina,
Blandizzi Corrado,
Tanini Marzia,
Vassalle Cristina,
Breschi Maria Cristina,
Tacca Mario Del
Publication year - 2005
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706053
Subject(s) - wortmannin , gastrin , endocrinology , mapk/erk pathway , medicine , prostaglandin , receptor , biology , receptor antagonist , kinase , cholecystokinin receptor , protein kinase b , chemistry , signal transduction , cholecystokinin , microbiology and biotechnology , antagonist , secretion
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 EP 4 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 (EP 4 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 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. 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 E 2 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 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.British Journal of Pharmacology (2005) 144 , 338–348. doi: 10.1038/sj.bjp.0706053