Author:
Guzman Juan,Weigelt Katrin,Neumann Angela,Tripal Philipp,Schmid Benjamin,Winter Zoltán,Palmisano Ralph,Culig Zoran,Cronauer Marcus V.,Muschler Paul,Wullich Bernd,Taubert Helge,Wach Sven
Abstract
Abstract
Background
The androgen/androgen receptor (AR)-signaling axis plays a central role in prostate cancer (PCa). Upon androgen-binding the AR dimerizes with another AR, and translocates into the nucleus where the AR-dimer activates/inactivates androgen-dependent genes. Consequently, treatments for PCa are commonly based on androgen deprivation therapy (ADT). The clinical benefits of ADT are only transitory and most tumors develop mechanisms allowing the AR to bypass its need for physiological levels of circulating androgens. Clinical failure of ADT is often characterized by the synthesis of a constitutively active AR splice variant, termed AR-V7. AR-V7 mRNA expression is considered as a resistance mechanism following ADT. AR-V7 no longer needs androgenic stimuli for nuclear entry and/or dimerization.
Methods
Our goal was to mechanistically decipher the interaction between full-length AR (AR-FL) and AR-V7 in AR-null HEK-293 cells using the NanoLuc Binary Technology under androgen stimulation and deprivation conditions.
Results
Our data point toward a hypothesis that AR-FL/AR-FL homodimers form in the cytoplasm, whereas AR-V7/AR-V7 homodimers localize in the nucleus. However, after androgen stimulation, all the AR-FL/AR-FL, AR-FL/AR-V7 and AR-V7/AR-V7 dimers were localized in the nucleus.
Conclusions
We showed that AR-FL and AR-V7 form heterodimers that localize to the nucleus, whereas AR-V7/AR-V7 dimers were found to localize in the absence of androgens in the nucleus.
Funder
Deutsche Forschungsgemeinschaft
Fonds für wissenschaftliche Forschung, Österreich
Fondation Cancer, Luxembourg
Wilhelm-Sander Stiftung
Universitätsklinikum Erlangen
Publisher
Springer Science and Business Media LLC
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