Regulation of Cox-2 by cyclic AMP response element binding protein in prostate cancer: potential role for nexrutine.
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.
Ghosh
Rita
R
The Sandra and Stanley Rosenberg Family Laboratories, Department of Urology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Garcia
Gretchen E
GE
Crosby
Katherine
K
Inoue
Hiroyasu
H
Thompson
Ian M
IM
Troyer
Dean A
DA
Kumar
Addanki P
AP
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
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