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

We recently showed that Nexrutine^R, 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 antiproliferative effects of Nexrutine ^R are mediated 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 E₂ (PGE₂) and suppresses apoptosis. Treatment of LNCaP cells with Nexrutine^R reduced tumor necrosis factor α-induced enzymatic as well as promoter activities of Cox-2. Nexrutine^R 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^R 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^R, demonstrating a prospective for development of Nexrutine^R for prostate cancer management.