title: Akt/cAMP-responsive element binding protein/cyclin D1 network: a novel target for prostate cancer inhibition in transgenic adenocarcinoma of mouse prostate model mediated by Nexrutine, a Phellodendron amurense bark extract.
abstract: OBJECTIVE
  Development of prostate cancer prevention strategies is an important priority to overcome high incidence, morbidity, and mortality. Recently, we showed that Nexrutine, an herbal extract, inhibits prostate cancer cell proliferation through modulation of Akt and cAMP-responsive element binding protein (CREB)-mediated signaling pathways. However, it is unknown if Nexrutine can be developed as a dietary supplement for the prevention of prostate cancer. In this study, we used the transgenic adenocarcinoma of mouse prostate (TRAMP) model to examine the ability of Nexrutine to protect TRAMP mice from developing prostate cancer.
  
  
  METHODS
  Eight-week-old TRAMP mice were fed with pelleted diet containing 300 and 600 mg/kg Nexrutine for 20 weeks. Efficacy of Nexrutine was evaluated by magnetic resonance imaging at 18 and 28 weeks of progression and histologic analysis of prostate tumor or tissue at the termination of the experiment. Tumor tissue was analyzed for modulation of various signaling molecules.
  
  
  RESULTS
  We show that Nexrutine significantly suppressed palpable tumors and progression of cancer in the TRAMP model. Expression of total and phosphorylated Akt, CREB, and cyclin D1 was significantly reduced in prostate tissue from Nexrutine intervention group compared with tumors from control animals. Nexrutine also inhibited cyclin D1 transcriptional activity in androgen-independent PC-3 cells. Overexpression of kinase dead Akt mutant or phosphorylation-defective CREB inhibited cyclin D1 transcriptional activity.
  
  
  CONCLUSIONS
  The current study shows that Nexrutine-mediated targeting of Akt/CREB-induced activation of cyclin D1 prevents the progression of prostate cancer. Expression of CREB and phosphorylated CREB increased in human prostate tumors compared with normal tissue, suggesting their potential use as prognostic markers.
authors.affiliation: Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. kumara3@uthscsa.edu
authors.forename: Addanki P
authors.initials: AP
authors.lastname: Kumar
authors.forename: Shylesh
authors.initials: S
authors.lastname: Bhaskaran
authors.forename: Manonmani
authors.initials: M
authors.lastname: Ganapathy
authors.forename: Katherine
authors.initials: K
authors.lastname: Crosby
authors.forename: Michael D
authors.initials: MD
authors.lastname: Davis
authors.forename: Peter
authors.initials: P
authors.lastname: Kochunov
authors.forename: John
authors.initials: J
authors.lastname: Schoolfield
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Dean A
authors.initials: DA
authors.lastname: Troyer
authors.forename: Rita
authors.initials: R
authors.lastname: Ghosh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D019938:Cyclin D1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D010936:Plant Extracts / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C512605:Nexrutine; D010936:Plant Extracts; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt