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 anti-proliferative 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 E-2 (PGE(2)) and suppresses apoptosis. Treatment of LNCaP cells with Nexrutine(R) reduced tumor necrosis factor A-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.