Regulation of Cox-2 by Cyclic AMP Response Element Binding Protein in Prostate Cancer: Potential Role for Nexrutine

• Published in: Neoplasia Vol. 9; no. 11; pp. 893 - 899
• Main Authors: Ghosh, Rita, Garcia, Gretchen E., Crosby, Katherine, Inoue, Hiroyasu, Thompson, Ian M., Troyer, Dean A., Kumar, Addanki P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2007; Elsevier BV; Neoplasia Press Inc; Elsevier
• Subjects: Brief; Cell Line, Tumor; Cox-2 promoter activity; CREB; Cyclic AMP Response Element-Binding Protein; Cyclic AMP Response Element-Binding Protein - analysis; Cyclic AMP Response Element-Binding Protein - physiology; Cyclooxygenase 2; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; DNA; DNA - metabolism; Humans; Immunohistochemistry; inflammation; Male; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; PGE2; Plant Extracts; Plant Extracts - pharmacology; Promoter Regions, Genetic; prostate cancer; Prostatic Neoplasms; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; RC254-282; Signal Transduction; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - pharmacology; Cox-2 promoter activity; PGE2; prostate cancer; CREB; inflammation
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.07502

We recently showed that NexrutineR, 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 NexrutineR 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 NexrutineR reduced tumor necrosis factor α-induced enzymatic as well as promoter activities of Cox-2. NexrutineR 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 NexrutineR 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 NexrutineR, demonstrating a prospective for development of NexrutineR for prostate cancer management.