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Molecular and Cellular Biology, February 2006, p. 929-939, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.929-939.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Shao-Yong Chen,1 Gerburg Wulf,1 Xiao Zhen Zhou,1 Mark A. Rubin,2 Kun Ping Lu,1 and Steven P. Balk1*

Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts,1 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts2

Received 18 May 2005/ Returned for modification 17 June 2005/ Accepted 7 November 2005

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

* Corresponding author. Mailing address: Cancer Biology Program, Hematology-Oncology Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. Phone: (617) 667-0878. Fax: (617) 667-5339. E-mail: sbalk{at}bidmc.harvard.edu.

Molecular and Cellular Biology, February 2006, p. 929-939, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.929-939.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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