Abstract
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 E2. 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 Ca2+/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 Ca2+/Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2.
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Acknowledgements
We are grateful to those who have helped us with different reagents. We also thank María Chorro, María Cazorla and Carmen Punzón for their excellent technical assistance and to Gloria Escribano for secretarial assistance. This work was supported by grants from the Ministerio de Educación y Ciencia-FEDER (BMC2001-0177), (SAF 2004-05109), (BFU2004-04157) and SAB 2001-0050; RECAVA cardiovascular network (C03/01) and RIS (G03/173) from Fondo de Investigaciones Sanitarias; Laboratorios del Dr ESTEVE; Comunidad de Madrid (08.3/0007/1) and Fundación Ramón Areces. This research was also supported by ECFP6 funding; EICOSANOX integrated project (LSH-CT-2004-005033); and MAIN network of excellence. The Commission is not liable for any use that may be made of information herein. RSC is a Member of Research Career from CONICET, Argentina.
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Corral, R., Iñiguez, M., Duque, J. et al. 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 26, 958–969 (2007). https://doi.org/10.1038/sj.onc.1209856
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DOI: https://doi.org/10.1038/sj.onc.1209856
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