NR5A2/HSD3B1 pathway promotes cellular resistance to second-generation antiandrogen darolutamide

This study investigated cellular mechanisms in steroidogenesis responsible for treatment resistance to the novel antiandrogen agent darolutamide in prostate cancer. HSD3B1 was overexpressed in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, HSD3B1 knoc...

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Veröffentlicht in:Drug resistance updates 2023-09, Vol.70, p.100990-100990, Article 100990
Hauptverfasser: Shiota, Masaki, Ushijima, Miho, Tsukahara, Shigehiro, Nagakawa, Shohei, Blas, Leandro, Takamatsu, Dai, Kobayashi, Satoshi, Matsumoto, Takashi, Inokuchi, Junichi, Eto, Masatoshi
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container_end_page 100990
container_issue
container_start_page 100990
container_title Drug resistance updates
container_volume 70
creator Shiota, Masaki
Ushijima, Miho
Tsukahara, Shigehiro
Nagakawa, Shohei
Blas, Leandro
Takamatsu, Dai
Kobayashi, Satoshi
Matsumoto, Takashi
Inokuchi, Junichi
Eto, Masatoshi
description This study investigated cellular mechanisms in steroidogenesis responsible for treatment resistance to the novel antiandrogen agent darolutamide in prostate cancer. HSD3B1 was overexpressed in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, HSD3B1 knockdown increased cellular sensitivity to darolutamide. Similarly, its upstream regulator NR5A2 was up-regulated in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, NR5A2 knockdown and NR5A2 inhibitor ML180 decreased expression of various steroidogenic enzymes including HSD3B1, leading to increased cellular sensitivity to darolutamide. The NR5A2/HSD3B1 pathway promoted cellular resistance to darolutamide and targeting NR5A2/HSD3B1 pathway is a promising therapeutic strategy to overcome darolutamide resistance.
doi_str_mv 10.1016/j.drup.2023.100990
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source ScienceDirect Journals (5 years ago - present)
subjects Androgen-deprivation therapy
Darolutamide
HSD3B1
NR5A2
Prostate cancer
title NR5A2/HSD3B1 pathway promotes cellular resistance to second-generation antiandrogen darolutamide
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