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 |
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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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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.</description><identifier>ISSN: 1368-7646</identifier><identifier>EISSN: 1532-2084</identifier><identifier>DOI: 10.1016/j.drup.2023.100990</identifier><identifier>PMID: 37478518</identifier><language>eng</language><publisher>Scotland: Elsevier Ltd</publisher><subject>Androgen-deprivation therapy ; Darolutamide ; HSD3B1 ; NR5A2 ; Prostate cancer</subject><ispartof>Drug resistance updates, 2023-09, Vol.70, p.100990-100990, Article 100990</ispartof><rights>2023 Elsevier Ltd</rights><rights>Copyright © 2023 Elsevier Ltd. 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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.</description><subject>Androgen-deprivation therapy</subject><subject>Darolutamide</subject><subject>HSD3B1</subject><subject>NR5A2</subject><subject>Prostate cancer</subject><issn>1368-7646</issn><issn>1532-2084</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kMlOxDAMhiMEYn8BDqhHLh3idEkjcYFhlRBILOeQJh7IqG2GJAXx9mQ0wJGTLevzL_sj5ADoBCjUx_OJ8eNiwigr0oAKQdfINlQFyxltyvXUF3WT87qst8hOCHNKAUohNslWwUveVNBsk5e7h-qUHV8_nhdnkC1UfPtUX9nCu95FDJnGrhs75TOPwYaoBo1ZdFlA7QaTv-KAXkXrhkwN0arBeJdmmVHedWNUvTW4RzZmqgu4_1N3yfPlxdP0Or-9v7qZnt7muqQ05tCgQAMttoYyZO2M84LqeqagZrSFtqK6EsCFaHnF6qZCEJXgKqGqEFCaYpccrXLT7e8jhih7G5bnqwHdGCRrSqAshfKEshWqvQvB40wuvO2V_5JA5dKsnMulWbk0K1dm09LhT_7Y9mj-Vn5VJuBkBWD68sOil0FbTMKM9aijNM7-l_8NwEOJ_Q</recordid><startdate>20230901</startdate><enddate>20230901</enddate><creator>Shiota, Masaki</creator><creator>Ushijima, Miho</creator><creator>Tsukahara, Shigehiro</creator><creator>Nagakawa, Shohei</creator><creator>Blas, Leandro</creator><creator>Takamatsu, Dai</creator><creator>Kobayashi, Satoshi</creator><creator>Matsumoto, Takashi</creator><creator>Inokuchi, Junichi</creator><creator>Eto, Masatoshi</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3306-4858</orcidid></search><sort><creationdate>20230901</creationdate><title>NR5A2/HSD3B1 pathway promotes cellular resistance to second-generation antiandrogen darolutamide</title><author>Shiota, Masaki ; Ushijima, Miho ; Tsukahara, Shigehiro ; Nagakawa, Shohei ; Blas, Leandro ; Takamatsu, Dai ; Kobayashi, Satoshi ; Matsumoto, Takashi ; Inokuchi, Junichi ; Eto, Masatoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-18e9ed1bebd02e2bf7730c6fa1620b1b50c591799b752685e19597a2e2a3914d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Androgen-deprivation therapy</topic><topic>Darolutamide</topic><topic>HSD3B1</topic><topic>NR5A2</topic><topic>Prostate cancer</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shiota, Masaki</creatorcontrib><creatorcontrib>Ushijima, Miho</creatorcontrib><creatorcontrib>Tsukahara, Shigehiro</creatorcontrib><creatorcontrib>Nagakawa, Shohei</creatorcontrib><creatorcontrib>Blas, Leandro</creatorcontrib><creatorcontrib>Takamatsu, Dai</creatorcontrib><creatorcontrib>Kobayashi, Satoshi</creatorcontrib><creatorcontrib>Matsumoto, Takashi</creatorcontrib><creatorcontrib>Inokuchi, Junichi</creatorcontrib><creatorcontrib>Eto, Masatoshi</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Drug resistance updates</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shiota, Masaki</au><au>Ushijima, Miho</au><au>Tsukahara, Shigehiro</au><au>Nagakawa, Shohei</au><au>Blas, Leandro</au><au>Takamatsu, Dai</au><au>Kobayashi, Satoshi</au><au>Matsumoto, Takashi</au><au>Inokuchi, Junichi</au><au>Eto, Masatoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NR5A2/HSD3B1 pathway promotes cellular resistance to second-generation antiandrogen darolutamide</atitle><jtitle>Drug resistance updates</jtitle><addtitle>Drug Resist Updat</addtitle><date>2023-09-01</date><risdate>2023</risdate><volume>70</volume><spage>100990</spage><epage>100990</epage><pages>100990-100990</pages><artnum>100990</artnum><issn>1368-7646</issn><eissn>1532-2084</eissn><abstract>This study investigated cellular mechanisms in steroidogenesis responsible for treatment resistance to the novel antiandrogen agent darolutamide in prostate cancer. 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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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