{
    "abstract": "Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer.\nLGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo. Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes.\nLGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo. LGR5 promoted the phosphorylation of glycogen synthase kinase-3\u03b2 (GSK-3\u03b2) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/\u03b2-catenin signaling pathway. The increased \u03b2-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide.\nLGR5 directly binds to HSP90AB1 and mediates GSK-3\u03b2 phosphorylation, promoting AR expression by regulating the WNT/\u03b2-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.",
    "authors": [
        {
            "affiliation": "Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nDepartment of Urology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.",
            "firstname": "Ze",
            "initials": "Z",
            "lastname": "Gao"
        },
        {
            "affiliation": "Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nDepartment of Urology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, China.\nGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.",
            "firstname": "Zhi",
            "initials": "Z",
            "lastname": "Xiong"
        },
        {
            "affiliation": "Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 528406, China.\nBiomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 528406, China.",
            "firstname": "Yiran",
            "initials": "Y",
            "lastname": "Tao"
        },
        {
            "affiliation": "Department of Urology, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong 510515, China.",
            "firstname": "Qiong",
            "initials": "Q",
            "lastname": "Wang"
        },
        {
            "affiliation": "Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.",
            "firstname": "Kaixuan",
            "initials": "K",
            "lastname": "Guo"
        },
        {
            "affiliation": "Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nGuangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.",
            "firstname": "Kewei",
            "initials": "K",
            "lastname": "Xu"
        },
        {
            "affiliation": "Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nGuangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.\nDepartment of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, Guangdong 511518, China.",
            "firstname": "Hai",
            "initials": "H",
            "lastname": "Huang"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2025 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.",
    "doi": "10.1097/CM9.0000000000003538\n10.3322/caac.21763\n10.1097/CM9.0000000000003442\n10.1016/j.bbcan.2021.188625\n10.1200/JCO.22.00970\n10.1200/JCO.23.00723\n10.1016/j.eururo.2023.04.002\n10.1016/j.drup.2023.100962\n10.3390/pharmaceutics14030498\n10.1056/NEJMoa1800536\n10.1200/JCO.19.00799\n10.1111/bju.13123\n10.1517/14656566.2013.775251\n10.1158/1078-0432.CCR-16-1357\n10.1016/S0140-6736(10)60172-9\n10.1056/NEJMoa1207506\n10.1038/s41417-021-00332-6\n10.1016/j.cell.2017.07.028\n10.1016/j.stem.2009.11.013\n10.1053/j.gastro.2022.07.081\n10.1038/nature06196\n10.1016/j.stem.2015.04.013\n10.1016/j.celrep.2012.12.017\n10.1016/j.celrep.2012.08.018\n10.1038/ncb3000\n10.1096/fj.201900082RR\n10.7150/thno.30562\n10.1002/path.5186\n10.1186/s13046-018-0864-6\n10.1186/s12943-020-01156-y\n10.1158/1535-7163.MCT-22-0415\n10.1038/s41417-020-00282-5\n10.1002/ctm2.191\n10.1093/annonc/mdv267\n10.1016/j.drup.2023.100985\n10.1186/s12885-021-07913-6\n10.1038/s41598-021-97351-y\n10.1186/s12885-020-06986-z\n10.1038/cddis.2017.393\n10.1016/j.cell.2022.03.011\n10.1038/s41575-022-00683-x\n10.1038/s41416-019-0442-5\n10.1016/j.tcb.2018.01.010\n10.1016/j.stemcr.2015.04.003\n10.1073/pnas.1908099116\n10.1016/j.bbrc.2011.08.136\n10.3390/jcm11216271\n10.1038/s41419-019-2141-9\n10.7150/thno.66148\n10.1038/s41388-018-0532-5\n10.1186/s12967-023-04288-z\n10.1053/j.gastro.2023.02.030\n10.1038/s41422-022-00645-7",
    "journal": "Chinese medical journal",
    "keywords": [
        "Enzalutamide",
        "Heat shock protein 90,000 alpha B1",
        "Leucine-rich repeated G-protein-coupled receptor 5",
        "Prostate cancer",
        "Treatment resistance"
    ],
    "methods": null,
    "publication_date": "2025-04-26",
    "pubmed_id": "40280884",
    "results": "LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo. LGR5 promoted the phosphorylation of glycogen synthase kinase-3\u03b2 (GSK-3\u03b2) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/\u03b2-catenin signaling pathway. The increased \u03b2-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide.",
    "title": "LGR5 interacts with HSP90AB1 to mediate enzalutamide resistance by activating the WNT/\u03b2-catenin/AR axis in prostate cancer.",
    "xml": "<Element 'PubmedArticle' at 0x788506fc0220>"
}