1,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growth.
Nurr1 is an orphan nuclear receptor and a member of the nerve growth factor I-B subfamily of transcription factors with no known endogenous ligand or stimulator. We show, for the first time, evidence that Nurr1 is expressed in a panel of 11 human bladder cancer cell lines. A new class of methylene-substituted diindolylmethanes (C-DIM) were screened and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) activated the ligand-binding domain of Nurr1. Treatment of bladder cancer cells with Nurr1-active C-DIM resulted in decreased cell survival (MTT assay) and induction of cell death pathways, resulting in poly(ADP-ribose) polymerase cleavage and DNA fragmentation. The specificity of the Nurr1-active compound was shown using RNA interference in 253J B-V cells, whereby small interfering RNA against Nurr1 attenuated ligand-dependent activation of Nurr1 and poly(ADP-ribose) polymerase cleavage. Furthermore, activation of Nurr1 resulted in stimulation of tumor necrosis factor-related apoptosis-inducing ligand and small interfering RNA experiments attenuated tumor necrosis factor-related apoptosis-inducing ligand production. In an orthotopic model of human bladder tumors established in nude mice, administration of a Nurr1-active C-DIM suppressed bladder cancer growth. These results identify Nurr1 as a potential target for bladder cancer therapy and also identify a novel agent for activating Nurr1.
Inamoto
Teruo
T
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Unit 1373, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Papineni
Sabitha
S
Chintharlapalli
Sudhakar
S
Cho
Sung-Dae
SD
Safe
Stephen
S
Kamat
Ashish M
AM
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D034622:RNA Interference; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
C534880:1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane; D001559:Benzhydryl Compounds; D004268:DNA-Binding Proteins; D007211:Indoles; D008024:Ligands; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; C022616:thiazolyl blue