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Neoplasia. 2007 Nov;9(11):893-9.

Regulation of Cox-2 by cyclic AMP response element binding protein in prostate cancer: potential role for nexrutine.

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  • 1The Sandra and Stanley Rosenberg Family Laboratories, Department of Urology, University of Texas Health Science Center, San Antonio, TX 78229, USA.

Abstract

We recently showed that Nexrutine, a Phellodendron amurense bark extract, suppresses proliferation of prostate cancer cell lines and tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Our data also indicate that the anti-proliferative effects of Nexrutine are emediated in part by Akt and Cyclic AMP response element binding protein (CREB). Cyclooxygenase (Cox-2), a pro-inflammatory mediator, is a CREB target that induces prostaglandin E(2) (PGE(2)) and suppresses apoptosis. Treatment of LNCaP cells with Nexrutine reduced tumor necrosis factor alpha-induced enzymatic as well as promoter activities of Cox-2. Nexrutine also reduced the expression and promoter activity of Cox-2 in PC-3 cells that express high constitutive levels of Cox-2. Deletion analysis coupled with mutational analysis of the Cox-2 promoter identified CRE as being sufficient for mediating Nexrutine response. Immunohistochemical analysis of human prostate tumors show increased expression of CREB and DNA binding activity in high-grade tumors (three-fold higher in human prostate tumors compared to normal prostate; P = .01). We have identified CREB-mediated activation of Cox-2 as a potential signaling pathway in prostate cancer which can be blocked with a nontoxic, cost-effective dietary supplement like Nexrutine, demonstrating a prospective for development of Nexrutine for prostate cancer management.

KEYWORDS:

CREB; Cox-2 promoter activity; PGE2; inflammation; prostate cancer

PMID:
18030357
[PubMed - indexed for MEDLINE]
PMCID:
PMC2077880
Free PMC Article
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