Journal
MOLECULAR ENDOCRINOLOGY
Volume 28, Issue 10, Pages 1729-1739Publisher
ENDOCRINE SOC
DOI: 10.1210/me.2014-1102
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Funding
- National Institutes of Health (NIH)/National Cancer Institute [R01-CA124998]
- NIH/National Institute of Environmental Health Sciences [P30-ES023512]
- Texas AgriLife
- NIH/National Center for Advancing Translational Sciences [UL1-TR001082]
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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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