title: Activation of nerve growth factor-induced B alpha by methylene-substituted diindolylmethanes in bladder cancer cells induces apoptosis and inhibits tumor growth.
abstract: Nerve growth factor-induced B (NGFI-B) genes are orphan nuclear receptors, and NGFI-B alpha (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-pPhOCH(3)) 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-pPhOCH(3)-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-pPhOCH(3) (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.
authors.affiliation: Department of Oral Pathology, School of Dentistry and Institute of Oral Biosciences, Brain Korea 21 Project, Chonbuk National University, Jeonju City, Republic of Korea.
authors.forename: Sung Dae
authors.initials: SD
authors.lastname: Cho
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Chintharlapalli
authors.forename: Maen
authors.initials: M
authors.lastname: Abdelrahim
authors.forename: Shaheen
authors.initials: S
authors.lastname: Khan
authors.forename: Kyungsil
authors.initials: K
authors.lastname: Yoon
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D011897:Random Allocation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D007211:Indoles; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C016392:3,3'-diindolylmethane