title: Regulation of Cox-2 by cyclic AMP response element binding protein in prostate cancer: potential role for nexrutine.
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.
authors.affiliation: The Sandra and Stanley Rosenberg Family Laboratories, Department of Urology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Ghosh
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Garcia
authors.forename: Katherine
authors.initials: K
authors.lastname: Crosby
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Inoue
authors.forename: Ian M
authors.initials: IM
authors.lastname: Thompson
authors.forename: Dean A
authors.initials: DA
authors.lastname: Troyer
authors.forename: Addanki P
authors.initials: AP
authors.lastname: Kumar
mesh_terms: D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C512605:Nexrutine; D010936:Plant Extracts; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human