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The nuclear orphan receptor NR4A1 regulates β1‐integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists
Author(s) -
Hedrick Erik,
Lee Syngook,
Safe Stephen
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22662
Subject(s) - gene knockdown , pancreatic cancer , integrin , biology , cancer research , focal adhesion , fibronectin , small interfering rna , cell migration , colorectal cancer , gene silencing , orphan receptor , receptor , microbiology and biotechnology , cancer , cell , transfection , signal transduction , biochemistry , gene , transcription factor , genetics
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‐pPhCO 2 Me) 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‐pPhCO 2 Me 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.