Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells.
Cyclooxygenase-2 (Cox-2), the gastrin-release peptide (GRP) and its cognate receptor (GRP-R) are overexpressed in a significant percentage of colorectal carcinomas and are associated with cell growth, invasiveness and tumor progression. However, a molecular link between all of them in adenocarcinomas has not been established. Here, we show that bombesin (BBS), a GRP homolog, stimulates the expression of Cox-2 mRNA and protein in human colon adenocarcinoma Caco-2 cells, resulting in enhanced release of prostaglandin E(2). These effects were markedly inhibited by the specific BBS antagonist RC-3940-II. BBS promotes the activation of the nuclear factor of activated T cells (NFAT) through a Ca(2+)/calcineurin (Cn)-linked pathway. Upon BBS stimulation, the NFATc1 isoform translocates into the nucleus with a concomitant increase in NFATc1 binding to two specific recognition sites in the promoter region of the Cox-2 gene. Furthermore, inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBS-stimulated cells. Interestingly, BBS pretreatment strongly enhances the invasive capacity of carcinoma cells, effect which was inhibited by a Cox-2-specific inhibitor. These findings provide the first evidence for the involvement of the Ca(2+)/Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2.
Corral
R S
RS
Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid-CSIC, Madrid, Spain.
Iñiguez
M A
MA
Duque
J
J
López-Pérez
R
R
Fresno
M
M
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000230:Adenocarcinoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D001839:Bombesin / Q000502:physiology*; D018938:Caco-2 Cells; D019703:Calcineurin / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004790:Enzyme Induction / Q000502:physiology; D006801:Humans; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D051546:Cyclooxygenase 2; D019703:Calcineurin; D001839:Bombesin