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Molecular Pharmacology

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Research ArticleArticle

Activation of Nerve Growth Factor-Induced Bα by Methylene-Substituted Diindolylmethanes in Bladder Cancer Cells Induces Apoptosis and Inhibits Tumor Growth

Sung Dae Cho, Syng-Ook Lee, Sudhakar Chintharlapalli, Maen Abdelrahim, Shaheen Khan, Kyungsil Yoon, Ashish M. Kamat and Stephen Safe
Molecular Pharmacology March 2010, 77 (3) 396-404; DOI: https://doi.org/10.1124/mol.109.061143
Sung Dae Cho
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Syng-Ook Lee
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Sudhakar Chintharlapalli
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Maen Abdelrahim
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Shaheen Khan
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Kyungsil Yoon
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Ashish M. Kamat
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Stephen Safe
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Abstract

Nerve growth factor-induced B (NGFI-B) genes are orphan nuclear receptors, and NGFI-Bα (Nur77, TR3) is overexpressed in bladder tumors and bladder cancer cells compared with nontumorous bladder tissue. 1,1-Bis(3′-indolyl)-1-(p-methoxyphenyl)-methane (DIM-C-pPhOCH3) and 1,1-bis(3′-indolyl)-1-(p-phenyl)methane have previously been identified as activators of Nur77, and both compounds inhibited growth and induced apoptosis of UC-5 and KU7 bladder cancer cells. The proapoptotic effects of methylene-substituted diindolylmethanes (C-DIMs) were unaffected by cotreatment with leptomycin B and were dependent on nuclear Nur77, and RNA interference with a small inhibitory RNA for Nur77 (iNur77) demonstrated that C-DIM-induced activation of apoptosis was Nur77-dependent. Microarray analysis of DIM-C-pPhOCH3-induced genes in UC-5 bladder cancer cells showed that this compound induced multiple Nur77-dependent proapoptotic or growth inhibitory genes including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), cystathionase, p21, p8, and sestrin-2. DIM-C-pPhOCH3 (25 mg/kg/d) also induced apoptosis and inhibited tumor growth in athymic nude mice bearing KU7 cells as xenografts, demonstrating that Nur77-active C-DIMs exhibit potential for bladder cancer chemotherapy by targeting Nur77, which is overexpressed in this tumor type.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This research was supported by the National Institutes of Health National Cancer Institute [01R01-CA124998], the Korea Research Foundation Grant, MOEHRD Basic Research Promotion Fund [Grant KRF-2008-331-E00260].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.061143

  • ABBREVIATIONS:

    NGFI-B
    nerve growth factor-induced B
    C-DIM
    methylene-substituted diindolylmethane
    DIM-C-pPhOCH3
    1,1-bis(3′-indolyl)-1-(p-methoxyphenyl)methane
    DIM-C-pPhC
    1,1-bis(3′-indolyl)-1-(p-chlorophenyl)methane
    TRAIL
    tumor necrosis factor-related apoptosis-inducing ligand
    IgG
    immunoglobulin G
    iNur77
    small inhibitory RNA for Nur77
    iScr
    nonspecific scrambled oligonucleotide
    NAG-1
    nonsteroidal anti-inflammatory drug activated gene
    DMSO
    dimethyl sulfoxide
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    TUNEL
    terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
    Z-VAD-fmk
    N-benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone
    PARP
    poly(ADP-ribose) polymerase.

    • Received September 17, 2009.
    • Accepted December 14, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (3)
Molecular Pharmacology
Vol. 77, Issue 3
1 Mar 2010
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Research ArticleArticle

Activation of Nerve Growth Factor-Induced Bα by Methylene-Substituted Diindolylmethanes in Bladder Cancer Cells Induces Apoptosis and Inhibits Tumor Growth

Sung Dae Cho, Syng-Ook Lee, Sudhakar Chintharlapalli, Maen Abdelrahim, Shaheen Khan, Kyungsil Yoon, Ashish M. Kamat and Stephen Safe
Molecular Pharmacology March 1, 2010, 77 (3) 396-404; DOI: https://doi.org/10.1124/mol.109.061143

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Research ArticleArticle

Activation of Nerve Growth Factor-Induced Bα by Methylene-Substituted Diindolylmethanes in Bladder Cancer Cells Induces Apoptosis and Inhibits Tumor Growth

Sung Dae Cho, Syng-Ook Lee, Sudhakar Chintharlapalli, Maen Abdelrahim, Shaheen Khan, Kyungsil Yoon, Ashish M. Kamat and Stephen Safe
Molecular Pharmacology March 1, 2010, 77 (3) 396-404; DOI: https://doi.org/10.1124/mol.109.061143
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