The nuclear orphan receptor NR4A1 regulates β1-integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists

Erik Hedrick, Syng Ook Lee, Stephen Safe

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

β1-Integrin is highly expressed and is a negative prognostic factor for colon and pancreatic cancer patients and the gene plays a functional role in cell migration and invasion. In this study, we demonstrate that β1-integrin expression is regulated in pancreatic and colon cancer cells by the pro-oncogenic orphan nuclear receptor 4A1 (NR4A1, Nur77, TR3) and knockdown of this receptor by RNA interference decreases β1-integrin protein and mRNA expression, α5-integrin, and also expression of β1-integrin-dependent phosphorylation of FAK (pFak). Knockdown of NR4A1 also decreased migration and fibronectin-induced adhesion in pancreatic (Panc1, L3.6 pL, and MiaPaCa2) and colon (RKO and SW480) cancer cells. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds containing p-hydroxy (DIM-C-pPhOH) and p-carbomethoxy (DIM-C-pPhCO2Me) groups are NR4A1 ligands that act as antagonists for this receptor. Treatment of pancreatic and colon cancer cells with DIM-C-pPhOH or DIM-C-pPhCO2Me mimics the effects of NR4A1 knockdown and decreases β1-integrin expression, β1-integrin regulated genes and responses including migration and adhesion. The results demonstrate a novel method for targeting β1-integrin in colon and pancreatic cancer cells and indicate possible clinical applications for C-DIM/NR4A1 antagonists for pancreatic and colon cancer therapy.

Original languageEnglish (US)
Pages (from-to)2066-2075
Number of pages10
JournalMolecular Carcinogenesis
Volume56
Issue number9
DOIs
StatePublished - Sep 2017

Keywords

  • C-DIM compounds
  • inhibition
  • migration
  • NR4A1
  • β1-integrin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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