1,1-Bis(3 '-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growth | Academic Article individual record

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.

author list (cited authors)
Inamoto, T., Papineni, S., Chintharlapalli, S., Cho, S., Safe, S., & Kamat, A. M.
publication date
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  • DNA-Binding Proteins
  • Thiazoles
  • Ligands
  • Urinary Bladder Neoplasms
  • Humans
  • Cell Survival
  • RNA Interference
  • Mice, Nude
  • Models, Biological
  • Cell Line, Tumor
  • Male
  • Tetrazolium Salts
  • Neoplasm Transplantation
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Transcription Factors
  • Indoles
  • Mice
  • Benzhydryl Compounds
  • Animals