期刊
MOLECULAR CARCINOGENESIS
卷 56, 期 9, 页码 2066-2075出版社
WILEY
DOI: 10.1002/mc.22662
关键词
beta 1-integrin; C-DIM compounds; inhibition; migration; NR4A1
资金
- National Institute of Environmental Health Sciences [P30-ES023512]
- Texas Agri-Life Research
beta 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 beta 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 beta 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-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 beta 1-integrin expression, 1-integrin regulated genes and responses including migration and adhesion. The results demonstrate a novel method for targeting beta 1-integrin in colon and pancreatic cancer cells and indicate possible clinical applications for C-DIM/NR4A1 antagonists for pancreatic and colon cancer therapy.
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