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

Oncogene. 2007 Feb 15;26(7):958-69. doi: 10.1038/sj.onc.1209856. Epub 2006 Aug 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Adenocarcinoma / enzymology*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Bombesin / physiology*
  • Caco-2 Cells
  • Calcineurin / physiology
  • Cell Movement / physiology*
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Induction / physiology
  • Humans
  • NFATC Transcription Factors / metabolism*
  • Neoplasm Invasiveness / pathology
  • Signal Transduction / physiology


  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • Cyclooxygenase 2
  • Calcineurin
  • Bombesin