Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. Scott M. Dehm, Donald J. Tindall, Departments of Urology, Biochemistry, and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN

Yingming Li, Kenneth S. Koeneman

Research output: Contribution to journalShort surveypeer-review

Abstract

Androgen ablation inhibits androgen receptor (AR) activity and is an effective treatment for advanced prostate cancer (PCa). Invariably, PCa relapses in a form resistant to further hormonal manipulations. Although this stage of the disease is androgen-refractory, or androgen depletion-independent (ADI), most tumors remain AR-dependent through aberrant mechanisms of AR activation. We employed the LNCaP/C4-2 model of PCa progression to study AR activity in androgen-dependent and ADI PCa cells. In this report, we show that the AR is transcriptionally inactive in androgen-dependent LNCaP cells in the absence of androgens. However, in ADI C4-2 cells, the AR displays a high level of constitutive, androgen-independent transcriptional activity. To study the mechanisms of ligand dependent and ligand-independent AR activation in these AR-expressing cells, we generated a reporter system based on swapping the DNA binding domain of the AR with the DNA binding domain of the yeast Gal4 transcription factor. In androgen-dependent PCa cells, the well characterized C-terminal AR activation function-2 (AF-2) domain was critical for strong, ligand-dependent activity. Conversely, in ADI PCa cells, constitutive, ligand-independent AR activity was AF-2- independent but instead dependent on N-terminal AR domains. Importantly, the ligand- and AF-2-independent mode of AR activation observed in ADI PCa cells was completely resistant to the antiandrogen, bicalutamide. Our data thus demonstrate that the AR can inappropriately activate transcription in ADI PCa cells via mechanisms that are resistant to castration and AR antagonism, the 2 modes of androgen ablation used to treat advanced PCa.

Original languageEnglish (US)
Pages (from-to)107
Number of pages1
JournalUrologic Oncology: Seminars and Original Investigations
Volume26
Issue number1
DOIs
StatePublished - Jan 2008

Bibliographical note

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Copyright 2009 Elsevier B.V., All rights reserved.

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