Activation of β-Catenin Signaling in Prostate Cancer by Peptidyl-Prolyl Isomerase Pin1-Mediated Abrogation of the Androgen Receptor-β-Catenin Interaction

Abstract

Androgen receptor (AR) interacts with β-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 β-catenin by inhibiting its binding to the adenomatous polyposis coli gene product and subsequent glycogen synthase kinase 3β (GSK-3β)-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 β-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-3β, Pin1 expression in LNCaP PCa cells, which are PTEN deficient, did not increase β-catenin. Instead, Pin1 expression markedly inhibited the β-catenin interaction with AR, and Pin1 abrogated the ability of AR to antagonize β-catenin/Tcf4 binding and transcriptional activity. These findings demonstrate that AR can suppress β-catenin signaling, that the AR-β-catenin interaction can be regulated by Pin1, and that abrogation of this interaction can enhance β-catenin/Tcf4 signaling and contribute to aggressive biological behavior in PCa.

We thank Lirim Shemshedini for plasmids, Xin Yuan for the CWR22D1 cells, Victoria Petkova for real-time RT-PCR, Meredith Regan for statistical analyses, Nicole McKnight for GST pull downs, Mike Stanbrough for help with figures, Eunis Choi for technical assistance, and Akihide Ryo for helpful discussions.

This work was supported by grants from the NIH (DK61047 to S.P.B., GM58556 to K.P.L., K08-CA093655 to G.W., CA022082 to X.Z.Z.), the Dana Farber/Harvard Cancer Center Prostate SPORE, and the Hershey Family Prostate Cancer Research Fund. S.-Y.C. was supported by a DOD Prostate Cancer Postdoctoral Award (PC040499). K.P.L. is a Pew Scholar and a Leukemia and Lymphoma Society Scholar.