1,1-Bis(3′-indolyl)-1-(p-substitutedphenyl)methanes are peroxisome proliferator-activated receptor γ agonists but decrease HCT-116 colon cancer cell survival through receptor-independent activation of early growth response-1 and nonsteroidal anti-inflammatory drug-activated gene-1

Sudhakar Chintharlapalli, Sabitha Papineni, Joon Baek Seung, Shengxi Liu, Stephen Safe

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

1,1-Bis-(3′-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC6H5) substituents decrease survival of HCT-116 colon cancer cells and activate peroxisome proliferator-activated receptor (PPAR) γ in this and other cancer cell lines. These PPARγ-active compounds had minimal effects on expression of cell cycle proteins and did not induce caveolin-1 in HCT-116 cells. However, these compounds induced nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) and apoptosis in HCT-116 cells, and in time-course studies, the PPARγ agonists maximally induced early growth response-1 (Egr-1) protein within 2 h, whereas a longer time course was observed for induction of NAG-1 protein. These data, coupled with deletion and mutation analysis of both the Egr-1 and NAG-1 gene promoters, indicate that activation of NAG-1 by these compounds was dependent on prior induction of Egr-1, and induction of these responses was PPARγ-independent. Results of kinase inhibitor studies also demonstrated that activation of Egr-1/NAG-1 by methylene-substituted diindolylmethanes (C-DIMs) was phosphatidylinositol 3-kinase-dependent, and this represents a novel receptor-independent pathway for C-DIM-induced growth inhibition and apoptosis in colon cancer cells.

Original languageEnglish (US)
Pages (from-to)1782-1792
Number of pages11
JournalMolecular Pharmacology
Volume68
Issue number6
DOIs
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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