Compound a inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression

Yichun Zheng, Hitoshi Ishiguro, Hiroki Ide, Satoshi Inoue, Eiji Kashiwagi, Takashi Kawahara, Mehrsa Jalalizadeh, Leonardo O. Reis, Hiroshi Miyamoto

Research output: Contribution to journalArticle

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/ARpositive cells, CpdA strongly inhibited cell proliferation and colony formation as well as increased G1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1_Mdecreased 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)- кB and activator protein 1 transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly, the expression of NF-кB-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-кB. 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.

Original languageEnglish (US)
Pages (from-to)1486-1497
Number of pages12
JournalMolecular Endocrinology
Volume29
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Glucocorticoid Receptors
Androgen Receptors
Urinary Bladder Neoplasms
Growth
Androgen Receptor Antagonists
Small Interfering RNA
Transcriptional Activation
Glucocorticoids
Dihydrotestosterone
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Transcription Factor AP-1
G1 Phase
Cytoplasmic and Nuclear Receptors
Reporter Genes
Heterografts
Dexamethasone
Vascular Endothelial Growth Factor A
Androgens
Cell Movement

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Zheng, Y., Ishiguro, H., Ide, H., Inoue, S., Kashiwagi, E., Kawahara, T., ... Miyamoto, H. (2015). Compound a inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression. Molecular Endocrinology, 29(10), 1486-1497. https://doi.org/10.1210/me.2015-1128

Compound a inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression. / Zheng, Yichun; Ishiguro, Hitoshi; Ide, Hiroki; Inoue, Satoshi; Kashiwagi, Eiji; Kawahara, Takashi; Jalalizadeh, Mehrsa; Reis, Leonardo O.; Miyamoto, Hiroshi.

In: Molecular Endocrinology, Vol. 29, No. 10, 01.10.2015, p. 1486-1497.

Research output: Contribution to journalArticle

Zheng, Y, Ishiguro, H, Ide, H, Inoue, S, Kashiwagi, E, Kawahara, T, Jalalizadeh, M, Reis, LO & Miyamoto, H 2015, 'Compound a inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression', Molecular Endocrinology, vol. 29, no. 10, pp. 1486-1497. https://doi.org/10.1210/me.2015-1128
Zheng, Yichun ; Ishiguro, Hitoshi ; Ide, Hiroki ; Inoue, Satoshi ; Kashiwagi, Eiji ; Kawahara, Takashi ; Jalalizadeh, Mehrsa ; Reis, Leonardo O. ; Miyamoto, Hiroshi. / Compound a inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression. In: Molecular Endocrinology. 2015 ; Vol. 29, No. 10. pp. 1486-1497.
@article{803c764e4c634100b93b3547a8b30d83,
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/ARpositive cells, CpdA strongly inhibited cell proliferation and colony formation as well as increased G1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1_Mdecreased 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)- кB and activator protein 1 transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly, the expression of NF-кB-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-кB. 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.",
author = "Yichun Zheng and Hitoshi Ishiguro and Hiroki Ide and Satoshi Inoue and Eiji Kashiwagi and Takashi Kawahara and Mehrsa Jalalizadeh and Reis, {Leonardo O.} and Hiroshi Miyamoto",
year = "2015",
month = "10",
day = "1",
doi = "10.1210/me.2015-1128",
language = "English (US)",
volume = "29",
pages = "1486--1497",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "10",

}

TY - JOUR

T1 - Compound a inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression

AU - Zheng, Yichun

AU - Ishiguro, Hitoshi

AU - Ide, Hiroki

AU - Inoue, Satoshi

AU - Kashiwagi, Eiji

AU - Kawahara, Takashi

AU - Jalalizadeh, Mehrsa

AU - Reis, Leonardo O.

AU - Miyamoto, Hiroshi

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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/ARpositive cells, CpdA strongly inhibited cell proliferation and colony formation as well as increased G1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1_Mdecreased 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)- кB and activator protein 1 transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly, the expression of NF-кB-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-кB. 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.

AB - 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/ARpositive cells, CpdA strongly inhibited cell proliferation and colony formation as well as increased G1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1_Mdecreased 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)- кB and activator protein 1 transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly, the expression of NF-кB-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-кB. 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.

UR - http://www.scopus.com/inward/record.url?scp=84943250294&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943250294&partnerID=8YFLogxK

U2 - 10.1210/me.2015-1128

DO - 10.1210/me.2015-1128

M3 - Article

C2 - 26322830

AN - SCOPUS:84943250294

VL - 29

SP - 1486

EP - 1497

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 10

ER -