title: Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction.
abstract: Androgen receptor (AR) interacts with beta-catenin and can suppress its coactivation of T cell factor 4 (Tcf4) in prostate cancer (PCa) cells. Pin1 is a peptidyl-prolyl cis/trans isomerase that stabilizes beta-catenin by inhibiting its binding to the adenomatous polyposis coli gene product and subsequent glycogen synthase kinase 3beta (GSK-3beta)-dependent degradation. Higher Pin1 expression in primary PCa is correlated with disease recurrence, and this study found that Pin1 expression was markedly increased in metastatic PCa. Consistent with this result, increased expression of Pin1 in transfected LNCaP PCa cells strongly accelerated tumor growth in vivo in immunodeficient mice. Pin1 expression in LNCaP cells enhanced beta-catenin/Tcf4 transcriptional activity, as assessed using Tcf4-regulated reporter genes, and increased expression of endogenous Tcf4 and c-myc. However, in contrast to results in cells with intact PTEN and active GSK-3beta, Pin1 expression in LNCaP PCa cells, which are PTEN deficient, did not increase beta-catenin. Instead, Pin1 expression markedly inhibited the beta-catenin interaction with AR, and Pin1 abrogated the ability of AR to antagonize beta-catenin/Tcf4 binding and transcriptional activity. These findings demonstrate that AR can suppress beta-catenin signaling, that the AR-beta-catenin interaction can be regulated by Pin1, and that abrogation of this interaction can enhance beta-catenin/Tcf4 signaling and contribute to aggressive biological behavior in PCa.
authors.affiliation: Cancer Biology Program, Hematology-Oncology Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Shao-Yong
authors.initials: SY
authors.lastname: Chen
authors.forename: Gerburg
authors.initials: G
authors.lastname: Wulf
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic; D014162:Transfection; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D059002:Androgen Receptor Antagonists; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011944:Receptors, Androgen; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D008156:Luciferases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse