Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and nuclear receptor-in dependent pathways | Academic Article individual record
abstract

Nerve growth factor-induced Balpha (NGFI-Balpha, Nur77) is an orphan nuclear receptor with no known endogenous ligands; however, recent studies on a series of methylene-substituted diindolylmethanes (C-DIM) have identified 1,1-bis(3'-indolyl)-1-(phenyl)methane (DIM-C-Ph) and 1,1-bis(3'-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) as Nur77 agonists. Nur77 is expressed in several colon cancer cell lines (RKO, SW480, HCT-116, HT-29, and HCT-15), and we also observed by immunostaining that Nur77 was overexpressed in colon tumors compared with normal colon tissue. DIM-C-Ph and DIM-C-pPhOCH3 decreased survival and induced apoptosis in RKO colon cancer cells, and this was accompanied by induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein. The induction of apoptosis and TRAIL by DIM-C-pPhOCH3 was significantly inhibited by a small inhibitory RNA for Nur77 (iNur77); however, it was evident from RNA interference studies that DIM-C-pPhOCH3 also induced Nur77-independent apoptosis. Analysis of DIM-C-pPhOCH3-induced gene expression using microarrays identified several proapoptotic genes, and analysis by reverse transcription-PCR in the presence or absence of iNur77 showed that induction of programmed cell death gene 1 was Nur77 dependent, whereas induction of cystathionase and activating transcription factor 3 was Nur77 independent. DIM-C-pPhOCH3 (25 mg/kg/d) also inhibited tumor growth in athymic nude mice bearing RKO cell xenografts. These results show that Nur77-active C-DIM compounds represent a new class of anti-colon cancer drugs that act through receptor-dependent and receptor-independent pathways.

authors
author list (cited authors)
Cho, S. D., Yoon, K., Chintharlapalli, S., Abdelrahim, M., Lei, P., Hamilton, S., ... Safe, S.
publication date
2007
published in
keywords
  • Colonic Neoplasms
  • Receptors, Cytoplasmic And Nuclear
  • Xenograft Model Antitumor Assays
  • Indoles
  • Mice
  • Apoptosis
  • Male
  • Transcription Factors
  • DNA-Binding Proteins
  • HT29 Cells
  • Animals
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Humans
  • HCT116 Cells
  • Receptors, Steroid
  • Methane
  • Mice, Nude
  • Gene Expression Regulation, Neoplastic