Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors

Kyungsil Yoon, Syng Ook Lee, Sung Dae Cho, Kyounghyun Kim, Shaheen Khan, Stephen Safe

Research output: Contribution to journalArticle

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Abstract

NR4A1 (Nur77, TR3) is overexpressed in pancreatic tumors and activation of TR3 by 1,1-bis(3′-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH3) inhibits cell and tumor growth and induces apoptosis. Microarray analysis demonstrates that in L3.6pL pancreatic cancer cells DIM-C-pPhOCH3 induces genes associated with metabolism, homeostasis, signal transduction, transcription, stress, transport, immune responses, growth inhibition and apoptosis. Among the most highly induced growth inhibitory and proapoptotic genes including activating transcription factor 3 (ATF3), p21, cystathionase, dual specificity phosphatase 1 and growth differentiation factor 15, RNA interference studies demonstrated that induction of all but the later gene by DIM-C-pPhOCH3 were TR3-dependent. We also observed that DIM-C-pPhOCH3 induced Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and induction of TRAIL was ATF3 dependent. Results of this and previous studies demonstrate that TR3 is unique among nuclear receptors since nuclear TR3 is activated or deactivated by diindolylmethane derivatives to induce different apoptotic and growth inhibitory pathways that inhibit pancreatic cancer cell and tumor growth.

Original languageEnglish (US)
Pages (from-to)836-842
Number of pages7
JournalCarcinogenesis
Volume32
Issue number6
DOIs
StatePublished - Jun 14 2011

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Pancreatic Neoplasms
Apoptosis
Activating Transcription Factor 3
Growth
Genes
Neoplasms
Growth Differentiation Factor 15
Dual Specificity Phosphatase 1
Cystathionine gamma-Lyase
Fas Ligand Protein
Methane
Microarray Analysis
Cytoplasmic and Nuclear Receptors
RNA Interference
Signal Transduction
Homeostasis
Tumor Necrosis Factor-alpha
diindolylmethane
Ligands

ASJC Scopus subject areas

  • Cancer Research

Cite this

Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors. / Yoon, Kyungsil; Lee, Syng Ook; Cho, Sung Dae; Kim, Kyounghyun; Khan, Shaheen; Safe, Stephen.

In: Carcinogenesis, Vol. 32, No. 6, 14.06.2011, p. 836-842.

Research output: Contribution to journalArticle

Yoon, Kyungsil ; Lee, Syng Ook ; Cho, Sung Dae ; Kim, Kyounghyun ; Khan, Shaheen ; Safe, Stephen. / Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors. In: Carcinogenesis. 2011 ; Vol. 32, No. 6. pp. 836-842.
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