PD05-02 TARGETING TR4 NUCLEAR RECEPTOR WITH ANTAGONIST BEXAROTENE INCREASES DOCETAXEL SENSITIVITY TO BETTER SUPPRESS THE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PROGRESSION

Abstract

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I (PD05)1 Sep 2021PD05-02 TARGETING TR4 NUCLEAR RECEPTOR WITH ANTAGONIST BEXAROTENE INCREASES DOCETAXEL SENSITIVITY TO BETTER SUPPRESS THE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PROGRESSION Linyi Hu, Yin Sun, Jie Luo, Xiang He, Meihua Ye, Gonghui Li, Yong Zhang, Jian Bai, Dahong Zhang, and Chawnshang Chang Linyi HuLinyi Hu More articles by this author , Yin SunYin Sun More articles by this author , Jie LuoJie Luo More articles by this author , Xiang HeXiang He More articles by this author , Meihua YeMeihua Ye More articles by this author , Gonghui LiGonghui Li More articles by this author , Yong ZhangYong Zhang More articles by this author , Jian BaiJian Bai More articles by this author , Dahong ZhangDahong Zhang More articles by this author , and Chawnshang ChangChawnshang Chang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001969.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Resistance to docetaxel (DTX) in metastatic castration-resistant prostate cancer (mCRPC) is a significant clinical problem as half of patients fail to respond to this therapy. The TR4 nuclear receptor has been reported to play an important role in prostate cancer (PCa) progression, however, its linkage to the DTX resistance remains unclear. Here we investigated the role of TR4 in DTX sensitivity in mCRPC cells and patients. Mechanism dissections revealed that TR4 might alter the DTX chemo-sensitivity via modulating the TR4/lincRNA-p21/HIF-1α/VEGF-A signaling. METHODS: We firstly investigated the TR4 expression in PCa cell lines (PC-3, Du-145, C4-2, and 22RV-1), non-tumor prostate cell lines (WPMY-1 and BPH-1), and human PCa clinical tissues from the public database Oncomine. Furthermore, we retrospectively investigated the TR4 expression through IHC staining in clinical samples from mCRPC patients treated with DTX chemotherapy. To confirm whether TR4 could influence chemo-sensitivity, we altered TR4 level in PCa cells. We also investigated the TR4 expression in DTX-resistant C4-2 and 22RV-1 cells, and its impact on tumor sphere formation and DTX-sensitivity. We established a reporter assay in PC-3 cells with the promoter of TR4 target gene (Oxytocin) and applied PITCh system with CRISPR-CAS9 technique to establish stable cell lines with luciferase inserted at the genomic location in the Oxytocin gene in 293T cells. These reporter systems were used to test whether Bexarotene (Bex, a derivative of retinoid) could influence DTX chemo-sensitivity through TR4 transactivation. Furthermore, based on bioinformatics prediction as well as chromatin-immunoprecipitation (ChIP) analysis, whether TR4 could regulate lincRNA-p21 expression via direct binding to the potential TR4-response-elements (TR4REs) upstream of lincRNA-p21 was tested. Newly identified TR4/lincRNA-p21/HIF-1alpha/VEGF-A signaling was also examined through gene correlation analysis based on mCRPC dataset from GEO, as well as HIF-1alpha inhibitor. The clinical significance of these findings was tested with staining of HIF-1α, VEGF-A, TR4 and P63 in mCRPC tissues between biopsy samples at first diagnosis and surgically resected samples after DTX treatment. RESULTS: We found TR4 was upregulated after DTX chemotherapy in the mCRPC cells and patients, and TR4 expression is correlated with DTX sensitivity with a higher level conferring chemo-resistance. Targeting TR4 with an antagonist Bexarotene suppressed the TR4 transactivation with increased DTX chemo-sensitivity. Mechanism dissection studies revealed that TR4 might alter the DTX chemo-sensitivity via modulating the TR4/lincRNA-p21/HIF-1α/VEGF-A signaling. CONCLUSIONS: We identify a novel role of TR4 that may function via altering the TR4/lincRNA-p21/HIF-1α/VEGF-A signaling to modulate the DTX-resistance in PCa, and targeting this newly identified signaling with Bex, a FDA-approved drug, may lead to increase DTX chemo-sensitivity to better suppress the mCRPC progression. Source of Funding: NIH grants (CA155477 and CA156700), George Whipple Professorship Endowment and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e55-e56 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Linyi Hu More articles by this author Yin Sun More articles by this author Jie Luo More articles by this author Xiang He More articles by this author Meihua Ye More articles by this author Gonghui Li More articles by this author Yong Zhang More articles by this author Jian Bai More articles by this author Dahong Zhang More articles by this author Chawnshang Chang More articles by this author Expand All Advertisement Loading ...