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This version published online on June 17, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0117
A more recent version of this article appeared on October 1, 2004
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Submitted on March 18, 2004
Accepted on June 7, 2004

Regulation of Androgen Receptor Signaling by PTEN Tumor Suppressor Through Distinct Mechanisms in Prostate Cancer Cells

HUI-KUAN LIN, YUEH-CHIANG HU, DONG KUN LEE, and CHAWNSHANG CHANG*

George Whipple Laboratory for Cancer Research. Departments of Urology, Pathology, Radiation Oncology, and The Cancer Center. University of Rochester, Rochester, NY 14642 (H.-K.L., Y.-C.H., D.K.L., C.C.)

* To whom correspondence should be addressed. E-mail: chang{at}urmc.rochester.edu.

Defects in the PTEN tumor suppressor gene have been found in many human cancers including breast and prostate. Here we show that PTEN suppresses androgen receptor (AR) activity via a PI3K/Akt-independent pathway in the early passage number of prostate cancer LNCP cells. We provide the direct links between PTEN and androgen/AR signaling by demonstrating that AR directly interacts with PTEN. The interaction between PTEN and AR inhibits the AR nuclear translocation and promotes the AR protein degradation that result in the suppression of AR transactivation and induction of apoptosis. The minimum interaction peptide within AR (aa, 483-651) disrupts the interaction of PTEN with AR and reduces the PTEN effect on AR transactivation and apoptosis. Genetic approaches using PTEN-null mouse embryonic fibroblasts (MEFs) further demonstrate that both AR expression and AR activity were much higher in PTEN-null MEFs than WT ones, and reintroducing PTEN into PTEN-null MEFs dramatically reduced AR protein levels and AR activity. Interestingly, we also found that PTEN could suppress AR activity via the PI3K/Akt-dependent pathway in the higher passage number LNCaP cells, since restoration of Akt activity blocks the effect of PTEN on AR activity. Together, these contrasting PTEN effects on AR activity in the same prostate cancer cell line with different passage numbers suggest that PTEN, via distinct mechanisms, differentially regulates AR in various stages of prostate cancers.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR
Coregulators:   PTEN
Ligands:   Dihydrotestosterone



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