title: Compound A Inhibits Bladder Cancer Growth Predominantly via Glucocorticoid Receptor Transrepression.
abstract: Recent evidence indicates that glucocorticoids (GCs) suppress bladder cancer cell invasion through the GC receptor (GR) pathway, whereas androgen-mediated androgen receptor (AR) signals induce bladder tumor progression. In this study, we assessed the effects of 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (compound A [CpdA]), which was shown to function as not only a GR modulator but also an AR antagonist, on the growth of bladder cancer. In GR/AR-positive cells, CpdA strongly inhibited cell proliferation and colony formation as well as increased G1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1μM decreased cell viability of TCCSUP/UMUC3-control-short hairpin RNA (shRNA), TCCSUP/UMUC3-GR-shRNA, and TCCSUP/UMUC3-AR-shRNA by 50%/67%, 25%/26%, and 38%/58%, respectively. CpdA also inhibited cell migration and invasion of GR/AR-positive (up to 61% decrease) and GR-positive/AR-silencing (up to 51% decrease) lines and, less strongly, those of GR-silencing/AR-positive lines (up to 35% decrease). Additionally, in UMUC3-control xenograft-bearing male mice, CpdA more strongly suppressed tumor growth than dexamethasone or hydroxyflutamide. In reporter gene assays, CpdA failed to induce GR transactivation, whereas it antagonized dihydrotestosterone-enhanced AR transactivation. In contrast, CpdA reduced nuclear factor (NF)-κB and activator protein 1 transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly, the expression of NF-κB-related molecules, matrix metalloproteinase-2, matrix metalloproteinase-9, interleukin-6, and vascular endothelial growth factor, was significantly down-regulated by CpdA in control lines but not in GR-silencing cells. Moreover, coimmunoprecipitation showed that CpdA promoted the interactions between GR and NF-κB. Thus, CpdA likely inhibits bladder cancer growth predominantly via inducing GR transrepression and at least partially mediated through the AR pathway, suggesting its effects more beneficial than GCs/pure GR ligands or AR antagonists.
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Yichun
authors: Y
authors: Zheng
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Hitoshi
authors: H
authors: Ishiguro
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Hiroki
authors: H
authors: Ide
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Satoshi
authors: S
authors: Inoue
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Eiji
authors: E
authors: Kashiwagi
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Takashi
authors: T
authors: Kawahara
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Mehrsa
authors: M
authors: Jalalizadeh
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Leonardo O
authors: LO
authors: Reis
authors: Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan.
authors: Hiroshi
authors: H
authors: Miyamoto
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014439:Tyramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D000726:Androgen Antagonists; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014439:Tyramine