Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling

Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cancers 2021-04, Vol.13 (7), p.1672
Hauptverfasser: Zhang, Xiong, Huang, Zenghong, Wang, Junjian, Ma, Zhao, Yang, Joy, Corey, Eva, Evans, Christopher P, Yu, Ai-Ming, Chen, Hong-Wu
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page
container_issue 7
container_start_page 1672
container_title Cancers
container_volume 13
creator Zhang, Xiong
Huang, Zenghong
Wang, Junjian
Ma, Zhao
Yang, Joy
Corey, Eva
Evans, Christopher P
Yu, Ai-Ming
Chen, Hong-Wu
description Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.
doi_str_mv 10.3390/cancers13071672
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8036795</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2520862500</sourcerecordid><originalsourceid>FETCH-LOGICAL-c421t-84a1034d4ad156cbe9c24a648d3230e9be0e68592fc3f8507500fbce169ef34c3</originalsourceid><addsrcrecordid>eNpdkc9OGzEQxq2qFUGUM7fKEpdeAv633t0LEkQNVImaKKVny-udTYw29mLvgvJcfQ-eCSNoRJnLjOTffONPH0InlJxxXpJzo52BECknOZU5-4QOGcnZWMpSfH43j9BxjHckFec0l_kBGqV1KjnLDlG41WENvXVrPAWoGx8edajx3Psu4qkPW6hxtcO_BtOCDngFBrrep2GxevqLtavxzDodAS-vZtg6vJ2slhP8aPsNvtl1ELTp7QPgyxX-bddOt-nQV_Sl0W2E47d-hP5Mf9xObsbzxfXPyeV8bASj_bgQmhIuaqFrmklTQWmY0FIUNWecQFkBAVlkJWsMb4qM5BkhTWWAyhIaLgw_Qhevut1QJRsGXB90q7pgtzrslNdW_f_i7Eat_YMqCJd5mSWB728Cwd8PEHu1tdFA22oHfoiKZYwUkqW7CT39gN75ISS_L5TIMyYZLRN1_kqZ4GMM0Ow_Q4l6iVR9iDRtfHvvYc__C5A_AwsdnkU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2547526219</pqid></control><display><type>article</type><title>Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling</title><source>PubMed Central Open Access</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Zhang, Xiong ; Huang, Zenghong ; Wang, Junjian ; Ma, Zhao ; Yang, Joy ; Corey, Eva ; Evans, Christopher P ; Yu, Ai-Ming ; Chen, Hong-Wu</creator><creatorcontrib>Zhang, Xiong ; Huang, Zenghong ; Wang, Junjian ; Ma, Zhao ; Yang, Joy ; Corey, Eva ; Evans, Christopher P ; Yu, Ai-Ming ; Chen, Hong-Wu</creatorcontrib><description>Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13071672</identifier><identifier>PMID: 33916325</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Androgen receptors ; Antagonists ; Apoptosis ; Cancer therapies ; Castration ; Cell culture ; Cell growth ; Genes ; Hyperactivity ; Inverse agonists ; Kinases ; Mesenchyme ; Metastases ; mRNA ; Oral administration ; Prostate cancer ; Protein-serine/threonine kinase ; Proteins ; Therapeutic targets ; Tumors ; Xenografts</subject><ispartof>Cancers, 2021-04, Vol.13 (7), p.1672</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-84a1034d4ad156cbe9c24a648d3230e9be0e68592fc3f8507500fbce169ef34c3</citedby><cites>FETCH-LOGICAL-c421t-84a1034d4ad156cbe9c24a648d3230e9be0e68592fc3f8507500fbce169ef34c3</cites><orcidid>0000-0002-5328-2908 ; 0000-0003-1441-4012 ; 0000-0002-9244-3807 ; 0000-0002-5957-7627</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036795/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036795/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33916325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Xiong</creatorcontrib><creatorcontrib>Huang, Zenghong</creatorcontrib><creatorcontrib>Wang, Junjian</creatorcontrib><creatorcontrib>Ma, Zhao</creatorcontrib><creatorcontrib>Yang, Joy</creatorcontrib><creatorcontrib>Corey, Eva</creatorcontrib><creatorcontrib>Evans, Christopher P</creatorcontrib><creatorcontrib>Yu, Ai-Ming</creatorcontrib><creatorcontrib>Chen, Hong-Wu</creatorcontrib><title>Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.</description><subject>Androgen receptors</subject><subject>Antagonists</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Castration</subject><subject>Cell culture</subject><subject>Cell growth</subject><subject>Genes</subject><subject>Hyperactivity</subject><subject>Inverse agonists</subject><subject>Kinases</subject><subject>Mesenchyme</subject><subject>Metastases</subject><subject>mRNA</subject><subject>Oral administration</subject><subject>Prostate cancer</subject><subject>Protein-serine/threonine kinase</subject><subject>Proteins</subject><subject>Therapeutic targets</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc9OGzEQxq2qFUGUM7fKEpdeAv633t0LEkQNVImaKKVny-udTYw29mLvgvJcfQ-eCSNoRJnLjOTffONPH0InlJxxXpJzo52BECknOZU5-4QOGcnZWMpSfH43j9BxjHckFec0l_kBGqV1KjnLDlG41WENvXVrPAWoGx8edajx3Psu4qkPW6hxtcO_BtOCDngFBrrep2GxevqLtavxzDodAS-vZtg6vJ2slhP8aPsNvtl1ELTp7QPgyxX-bddOt-nQV_Sl0W2E47d-hP5Mf9xObsbzxfXPyeV8bASj_bgQmhIuaqFrmklTQWmY0FIUNWecQFkBAVlkJWsMb4qM5BkhTWWAyhIaLgw_Qhevut1QJRsGXB90q7pgtzrslNdW_f_i7Eat_YMqCJd5mSWB728Cwd8PEHu1tdFA22oHfoiKZYwUkqW7CT39gN75ISS_L5TIMyYZLRN1_kqZ4GMM0Ow_Q4l6iVR9iDRtfHvvYc__C5A_AwsdnkU</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Zhang, Xiong</creator><creator>Huang, Zenghong</creator><creator>Wang, Junjian</creator><creator>Ma, Zhao</creator><creator>Yang, Joy</creator><creator>Corey, Eva</creator><creator>Evans, Christopher P</creator><creator>Yu, Ai-Ming</creator><creator>Chen, Hong-Wu</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5328-2908</orcidid><orcidid>https://orcid.org/0000-0003-1441-4012</orcidid><orcidid>https://orcid.org/0000-0002-9244-3807</orcidid><orcidid>https://orcid.org/0000-0002-5957-7627</orcidid></search><sort><creationdate>20210401</creationdate><title>Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling</title><author>Zhang, Xiong ; Huang, Zenghong ; Wang, Junjian ; Ma, Zhao ; Yang, Joy ; Corey, Eva ; Evans, Christopher P ; Yu, Ai-Ming ; Chen, Hong-Wu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-84a1034d4ad156cbe9c24a648d3230e9be0e68592fc3f8507500fbce169ef34c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Androgen receptors</topic><topic>Antagonists</topic><topic>Apoptosis</topic><topic>Cancer therapies</topic><topic>Castration</topic><topic>Cell culture</topic><topic>Cell growth</topic><topic>Genes</topic><topic>Hyperactivity</topic><topic>Inverse agonists</topic><topic>Kinases</topic><topic>Mesenchyme</topic><topic>Metastases</topic><topic>mRNA</topic><topic>Oral administration</topic><topic>Prostate cancer</topic><topic>Protein-serine/threonine kinase</topic><topic>Proteins</topic><topic>Therapeutic targets</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Xiong</creatorcontrib><creatorcontrib>Huang, Zenghong</creatorcontrib><creatorcontrib>Wang, Junjian</creatorcontrib><creatorcontrib>Ma, Zhao</creatorcontrib><creatorcontrib>Yang, Joy</creatorcontrib><creatorcontrib>Corey, Eva</creatorcontrib><creatorcontrib>Evans, Christopher P</creatorcontrib><creatorcontrib>Yu, Ai-Ming</creatorcontrib><creatorcontrib>Chen, Hong-Wu</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Xiong</au><au>Huang, Zenghong</au><au>Wang, Junjian</au><au>Ma, Zhao</au><au>Yang, Joy</au><au>Corey, Eva</au><au>Evans, Christopher P</au><au>Yu, Ai-Ming</au><au>Chen, Hong-Wu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2021-04-01</date><risdate>2021</risdate><volume>13</volume><issue>7</issue><spage>1672</spage><pages>1672-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33916325</pmid><doi>10.3390/cancers13071672</doi><orcidid>https://orcid.org/0000-0002-5328-2908</orcidid><orcidid>https://orcid.org/0000-0003-1441-4012</orcidid><orcidid>https://orcid.org/0000-0002-9244-3807</orcidid><orcidid>https://orcid.org/0000-0002-5957-7627</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2072-6694
ispartof Cancers, 2021-04, Vol.13 (7), p.1672
issn 2072-6694
2072-6694
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8036795
source PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Androgen receptors
Antagonists
Apoptosis
Cancer therapies
Castration
Cell culture
Cell growth
Genes
Hyperactivity
Inverse agonists
Kinases
Mesenchyme
Metastases
mRNA
Oral administration
Prostate cancer
Protein-serine/threonine kinase
Proteins
Therapeutic targets
Tumors
Xenografts
title Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T02%3A50%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20Feedforward%20Loops%20Formed%20by%20Nuclear%20Receptor%20ROR%CE%B3%20and%20Kinase%20PBK%20in%20mCRPC%20with%20Hyperactive%20AR%20Signaling&rft.jtitle=Cancers&rft.au=Zhang,%20Xiong&rft.date=2021-04-01&rft.volume=13&rft.issue=7&rft.spage=1672&rft.pages=1672-&rft.issn=2072-6694&rft.eissn=2072-6694&rft_id=info:doi/10.3390/cancers13071672&rft_dat=%3Cproquest_pubme%3E2520862500%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2547526219&rft_id=info:pmid/33916325&rfr_iscdi=true