PT - JOURNAL ARTICLE AU - Sung Dae Cho AU - Syng-Ook Lee AU - Sudhakar Chintharlapalli AU - Maen Abdelrahim AU - Shaheen Khan AU - Kyungsil Yoon AU - Ashish M. Kamat AU - Stephen Safe TI - Activation of Nerve Growth Factor-Induced Bα by Methylene-Substituted Diindolylmethanes in Bladder Cancer Cells Induces Apoptosis and Inhibits Tumor Growth AID - 10.1124/mol.109.061143 DP - 2010 Mar 01 TA - Molecular Pharmacology PG - 396--404 VI - 77 IP - 3 4099 - http://molpharm.aspetjournals.org/content/77/3/396.short 4100 - http://molpharm.aspetjournals.org/content/77/3/396.full SO - Mol Pharmacol2010 Mar 01; 77 AB - 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.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics