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Modulation of Androgen Receptor Transactivation by Gelsolin

A Newly Identified Androgen Receptor Coregulator¹

George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Cancer Center, University of Rochester Medical Center, Rochester, New York 14642 [H-J. T., H-Y. K., H-C. C., S. Y., H. M., C. C.], and Departments of Urology and Pathology, Graduate School of Medicine, Osaka University, Yamadaoka, Suita 565-0871, Japan [K. N., Y. H., T. T., N. N., M. S., K. A., A. O.]

The partial agonist effect of antiandrogens has been well documented, and such effect is amplified by derived mutant androgen receptors (ARs) in prostate cancer cells. Here we report the identification of gelsolin (GSN) as an AR-associated protein. Hydroxyflutamide (HF), as well as androgens, can promote the interaction between AR and GSN in a dose-dependent manner. GSN interacts with AR DNA-binding domain and ligand-binding domain via its COOH-terminal domain. Immunolocalization studies show that GSN interacts with AR during nuclear translocation. Functional analyses additionally demonstrate that GSN enhances AR activity in the presence of either androgen or HF. Two peptides representing partial regions of the AR DNA-binding domain and the ligand-binding domain can block the GSN-enhanced AR activity. The expression of GSN is enhanced in LNCaP cells, LNCaP xenografts, and human prostate tumors after androgen depletion. Increasing expression of GSN enhances the AR activity in the presence of HF. Together, these data suggest that the weak androgenic effect of HF may be amplified by increasing the amount of GSN after androgen ablation treatment. Therefore, blockage of the interaction between AR and GSN could become a potential therapeutic target for the treatment of prostate cancer.

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