Mechanism of antiandrogen action: key role of Hsp90 in conformational change and transcriptional activity of the androgen receptor.

Georget, Virginie; Térouanne, Béatrice; Nicolas, Jean-Claude; Sultan, Charles

doi:10.1021/bi0259150

Cited by 170Heat shock proteins researchProstate Cancer Treatment and ResearchEstrogen and related hormone effects

Mechanism of antiandrogen action: key role of Hsp90 in conformational change and transcriptional activity of the androgen receptor.

Georget, Virginie, Térouanne, Béatrice, Nicolas, Jean-Claude, Sultan, Charles·2002·Biochemistry

DOI 10.1021/bi0259150

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Abstract

Activation of the androgen receptor (AR) is induced by ligand binding through conformational changes leading to control of gene expression. Antiandrogens compete with androgens for AR occupancy and subsequently block at least one step in AR action. Analysis of nuclear transfer kinetics using the GFP-AR fusion protein and partial proteolysis analysis provided evidence that the ligand-bound receptor was in equilibrium between at least two distinct conformations, leading to the production of 35 and 29 kDa trypsin-resistant fragments. It also indicated that this equilibrium may regulate the rate of nuclear transfer. The slowing of nuclear transfer by antiandrogens was correlated with the amount of receptor in conformation leading to the 35 kDa trypsin-resistant fragment. To establish the role of heat shock protein (hsp) 90 activity in antiandrogenic action, the effect of geldanamycin (GA) was evaluated in both in vitro assays and live cells. We demonstrated that in vitro hsp90s are required to stabilize the receptor in the inactive conformation and that hsp90 activity is involved in the integrity and nuclear transfer of agonist- and antagonist-bound AR. Furthermore, nuclear transfer is not the only step affected by GA since this compound was also active on a constitutively nuclear AR (GFP-NLS-AR). Hsp90 inactivation impedes interaction of androgen-bound GFP-NLS-AR with nuclear components and inhibits transcriptional activity. We conclude that hsp90s are required for the acquisition of active conformation in agonist-bound AR to regulate nuclear transfer, nuclear matrix binding, and transcriptional activity. Pure antiandrogens block the transconformational change of AR in an intermediary complex unable to acquire the active conformation and to dissociate the hsp90.

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Hsp90 holds the androgen receptor in a permissible conformation that allows efficient binding to DHT.
“Hsp90 has also been demonstrated to hold the AR in a permissible conformation that allows for efficient binding to DHT (62).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [62]

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Untitled work
Sánchez (2002) · doi:10.1379/1466-1268(2002)007
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Authors: Georget, V., Térouanne, B., Nicolas, J.-C., & Sultan, C.
Affiliations: Inserm (FR)
Corresponding author: Sultan, Charles
ORCID: Georget, Virginie
Venue: Biochemistry
Publisher: American Chemical Society (ACS)
Published: 2002-09-04
Volume: 41
Issue: 39
Pages: 11824-11831
ISSN: 0006-2960 (ISSN-L)
1520-4995
DOI: 10.1021/bi0259150
OpenAlex: W1990534307
Cited by: 168
References: 11
Citations by year: 2026: 1 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 8 · 2016: 2 · 2015: 6 · 2014: 10 · 2013: 3 · 2012: 5
FWCI: 3.01
Type: journal article
Language: en
Open access: closed
Locations: Biochemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords: androgen receptor, androgen receptor antagonists, HSP90, geldanamycin, receptor conformational change, nuclear translocation, transcriptional activity, ligand binding
MeSH terms: Androgen Antagonists, Animals, Cell Line, Cell Nucleus, Humans, Hydrolysis, Kinetics, Luminescent Proteins, Microscopy, Fluorescence, Endopeptidases, Plasmids, Protein Conformation, Quinones, Receptors, Androgen, Transfection, Trans-Activators, Benzoquinones, HSP90 Heat-Shock Proteins, COS Cells, Active Transport, Cell Nucleus, Lactams, Macrocyclic, Green Fluorescent Proteins

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Mechanism of antiandrogen action: key role of Hsp90 in conformational change and transcriptional activity of the androgen receptor.

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