Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and nuclear receptor-independent pathways

Dae Cho Sung, Kyungsil Yoon, Sudhakar Chintharlapalli, Maen Abdelrahim, Ping Lei, Stanley Hamilton, Shaheen Khan, Shashi K. Ramaiah, Stephen Safe

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Nerve growth factor-induced Bα (NGFI-Bα, 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.

Original languageEnglish (US)
Pages (from-to)674-683
Number of pages10
JournalCancer research
Volume67
Issue number2
DOIs
StatePublished - Jan 15 2007

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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