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
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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
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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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