The nuclear orphan receptor NR4A1 regulates 1-integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists.
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1-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 1-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 1-integrin protein and mRNA expression, 5-integrin, and also expression of 1-integrin-dependent phosphorylation of FAK (pFak). Knockdown of NR4A1 also decreased migration and fibronectin-induced adhesion in pancreatic (Panc1, L3.6pL, 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-pPhCO2 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-pPhCO2 Me mimics the effects of NR4A1 knockdown and decreases 1-integrin expression, 1-integrin regulated genes and responses including migration and adhesion. The results demonstrate a novel method for targeting 1-integrin in colon and pancreatic cancer cells and indicate possible clinical applications for C-DIM/NR4A1 antagonists for pancreatic and colon cancer therapy.
