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Mol Endocrinol. 2014 Oct;28(10):1729-39. doi: 10.1210/me.2014-1102. Epub 2014 Aug 6.

Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells.

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Department of Food Science and Technology (S.-O.L.), Keimyung University, Daegu 704-701, Republic of Korea; College of Medicine (X.L.), Texas A&M Health Science Center, and Department of Veterinary Physiology and Pharmacology (E.H., S.S.), Texas A&M University, College Station, TX 77843; Institute of Bioscience and Technology (U.-H.J., S.S.), Texas A&M Health Science Center, Houston, Texas 77030; Center for Environmental Medicine (R.B.T.), Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523; Department of Pharmaceutical Sciences (D.S.B.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; and School of Life Sciences (L.L., Y.Z., Q.W.), University of Xiamen, Xiamen, 361005 Fujian, China.


1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds exhibit antineoplastic activity in multiple cancer cell lines and the p-hydroxyphenyl analog (DIM-C-pPhOH) inactivates nuclear receptor 4A1 (NR4A1) in lung and pancreatic cancer cell lines. Using a series of 14 different p-substituted phenyl C-DIMs, we show that several compounds including DIM-C-pPhOH directly interacted with the ligand binding domain of NR4A1. Computational-based molecular modeling studies showed high-affinity interactions of DIM-C-pPhOH and related compounds within the ligand binding pocket of NR4A1, and these same compounds decreased NR4A1-dependent transactivation in colon cancer cells transfected with a construct containing 3 tandem Nur77 binding response elements linked to a luciferase reporter gene. Moreover, we also show that knockdown of NR4A1 by RNA interference (small interfering NR4A1) or treatment with DIM-C-pPhOH and related compounds decreased colon cancer cell growth, induced apoptosis, decreased expression of survivin and other Sp-regulated genes, and inhibited mammalian target of rapamycin signaling. Thus, C-DIMs such as DIM-C-pPhOH directly bind NR4A1 and are NR4A1 antagonists in colon cancer cells, and their antineoplastic activity is due, in part, to their interactions with nuclear NR4A1.

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