title: Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator.
abstract: 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.
authors.affiliation: Department of Urology, Graduate School of Medicine, Osaka University, Yamadaoka, Suita 565-0871, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nishimura
authors.forename: Huei-Ju
authors.initials: HJ
authors.lastname: Ting
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Harada
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokizane
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Hong-Yo
authors.initials: HY
authors.lastname: Kang
authors.forename: Hong-Chiang
authors.initials: HC
authors.lastname: Chang
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Masaru
authors.initials: M
authors.lastname: Shin
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Aozasa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuyama
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D019556:COS Cells; D003001:Cloning, Molecular; D013196:Dihydrotestosterone / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D018260:Gelsolin / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018260:Gelsolin; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D005485:Flutamide