Author:
Wen Xiaodong,Chao Celia,Ives Kirk,Hellmich Mark R
Abstract
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.
Publisher
Springer Science and Business Media LLC
Reference50 articles.
1. di Sant'Agnese PA, de Mesy Jensen KL, Ackroyd RK: Calcitonin, katacalcin, and calcitonin gene-related peptide in the human prostate. An immunocytochemical and immunoelectron microscopic study. Arch Pathol Lab Med. 1989, 113 (7): 790-796.
2. Iwamura M, Wu G, Abrahamsson PA, di Sant'Agnese PA, Cockett AT, Deftos LJ: Parathyroid hormone-related protein is expressed by prostatic neuroendocrine cells. Urology. 1994, 43 (5): 667-674. 10.1016/0090-4295(94)90182-1
3. Vashchenko N, Abrahamsson PA: Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities. Eur Urol. 2005, 47 (2): 147-155. 10.1016/j.eururo.2004.09.007
4. Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H: Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate. 2000, 42 (1): 73-78. 10.1002/(SICI)1097-0045(20000101)42:1<73::AID-PROS9>3.0.CO;2-G
5. Rubio J, Ramos D, Lopez-Guerrero JA, Iborra I, Collado A, Solsona E, Almenar S, Llombart-Bosch A: Immunohistochemical expression of Ki-67 antigen, cox-2 and Bax/Bcl-2 in prostate cancer; prognostic value in biopsies and radical prostatectomy specimens. Eur Urol. 2005, 48 (5): 745-751. 10.1016/j.eururo.2005.06.014
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