title: Enzalutamide inhibits proliferation of gemcitabine-resistant bladder cancer cells with increased androgen receptor expression.
abstract: Advanced bladder cancer is treated mainly with gemcitabine and cisplatin, but most patients eventually become resistance. Androgen receptor (AR) signaling has been implicated in bladder cancer as well as other types of cancer including prostate cancer. In this study, we investigated the expression and role of AR in gemcitabine-resistant bladder cancer cells and also the potential of enzalutamide, an AR inhibitor, as a therapeutic for the chemoresistance. First of all, we established gemcitabine-resistant T24 cells (T24GR) from T24 bladder cancer cells and performed gene expression profiling. Microarray analysis revealed upregulation of AR expression in T24GR cells compared with T24 cells. AR mRNA and protein expression was confirmed to be increased in T24GR cells, respectively, by quantitative RT-PCR and western blot analysis, which was associated with more potent AR transcriptional activity as measured by luciferase reporter assay. The copy number of AR gene in T24GR cells determined by PCR was twice as many as that of T24 cells. AR silencing by siRNA transfection resulted in inhibition of proliferation of T24GR cells. Cell culture in charcoal-stripped serum and treatment with enzalutamide inhibited growth of T24GR cells, which was accompanied by cell cycle arrest. AR transcriptional activity was found to be reduced in T24GR cells by enzalutamide treatment. Lastly, enzalutamide also inhibited cell proliferation of HTB5 bladder cancer cells that express AR and possess intrinsic resistance to gemcitabine. Our results suggest that enzalutamide may have the potential to treat patients with advanced gemcitabine-resistant bladder cancer with increased AR expression.
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kameyama
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Horie
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kato
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Kyojiro
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Health Support Center, Toyohashi University of Technology, Tenpaku-cho, Toyohashi, Aichi 441-8580, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Division of Pathology, Gifu University Hospital, Gifu, Gifu 501-1194, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Deguchi
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D000728:Androgens / Q000235:genetics / Q000378:metabolism; D001549:Benzamides; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000093542:Gemcitabine
chemical_list: C410798:AR protein, human; D000728:Androgens; D001549:Benzamides; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D003841:Deoxycytidine; D010669:Phenylthiohydantoin; C540278:enzalutamide; D000093542:Gemcitabine