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Open Access Highly Accessed Research article

Regulation of bombesin-stimulated cyclooxygenase-2 expression in prostate cancer cells

Xiaodong Wen1, Celia Chao13, Kirk Ives1 and Mark R Hellmich123*

Author Affiliations

1 Department of Surgery, Univ. of Texas Medical Branch, 301 Univ. Blvd., Galveston, TX 77555, USA

2 Neuroscience and Cell Biology, Univ. of Texas Medical Branch, 301 Univ. Blvd., Galveston, TX 77555, USA

3 Sealy Center for Cancer Cell Biology, Univ. of Texas Medical Branch, 301 Univ. Blvd., Galveston, TX 77555, USA

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BMC Molecular Biology 2011, 12:29  doi:10.1186/1471-2199-12-29

Published: 11 July 2011

Abstract

Background

Cyclooxygenase-2 (COX-2) and the bombesin (BBS)-like peptide, gastrin-releasing peptide (GRP), have been implicated in the progression of hormone-refractory prostate cancer; however, a mechanistic link between the bioactive peptide and COX-2 expression in prostate cells has not been made.

Results

We report that BBS stimulates COX-2 mRNA and protein expression, and the release of prostaglandin E2 from the GRP receptor (GRPR)-positive, androgen-insensitive prostate cancer cell line, PC-3. BBS-stimulated COX-2 expression is mediated, in part, by p38MAPK and PI3 kinase (PI3K)/Akt pathways, and blocked by a GRPR antagonist. The PI3K/Akt pathway couples GRPR to the transcription factor, activator protein-1 (AP-1), and enhanced COX-2 promoter activity. Although BBS stimulates nuclear factor-kappaB (NF-κB) in PC-3, NF-κB does not regulate GRPR-mediated COX-2 expression. The p38MAPK pathway increases BBS-stimulated COX-2 expression by slowing the degradation of COX-2 mRNA. Expression of recombinant GRPR in the androgen-sensitive cell line LNCaP is sufficient to confer BBS-stimulated COX-2 expression via the p38MAPK and PI3K/Akt pathways.

Conclusions

Our study establishes a mechanistic link between GRPR activation and enhanced COX-2 expression in prostate cancer cell lines, and suggests that inhibiting GRPR may, in the future, provide an effective therapeutic alternative to non-steroidal anti-inflammatory drugs for inhibiting COX-2 in patients with recurrent prostate cancer.

Keywords:
gastrin-releasing peptide receptor; signal transduction; prostate cancer; neuroendocrine differentiation; hormone-refractory