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

Authors

• Syng-Ook Lee, 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.
• Xi Li
• Erik Hedrick
• Un-Ho Jin
• Ronald B. Tjalkens
• Donald S. Backos
• Li Li
• Yi Zhang
• Qiao Wu
• Stephen Safe

Document Type

Article

Abstract

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.

Medical Subject Headings

Cell Line, Tumor; Colonic Neoplasms (drug therapy, metabolism); Humans; Indoles (pharmacology, therapeutic use); Models, Molecular; Nuclear Receptor Subfamily 4, Group A, Member 1 (antagonists & inhibitors, metabolism); Phenols (pharmacology, therapeutic use); RNA Interference

Publication Date

10-1-2014

Publication Title

Molecular endocrinology (Baltimore, Md.)

E-ISSN

1944-9917

Volume

28

Issue

10

First Page

1729

Last Page

39

PubMed ID

25099012

Digital Object Identifier (DOI)

10.1210/me.2014-1102

Recommended Citation

Lee, Syng-Ook; Li, Xi; Hedrick, Erik; Jin, Un-Ho; Tjalkens, Ronald B.; Backos, Donald S.; Li, Li; Zhang, Yi; Wu, Qiao; and Safe, Stephen, "Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells" (2014). Translational Neuroscience. 2516.
https://scholar.barrowneuro.org/neurobiology/2516