2. Academic Validation
  3. Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

  • PLoS One. 2015 Jun 2;10(6):e0128308. doi: 10.1371/journal.pone.0128308.
Erik Hedrick 1,  Syng-Ook Lee 2,  Gyungeun Kim 3,  Maen Abdelrahim 4,  Un-Ho Jin 5,  Stephen Safe 5,  Ala Abudayyeh 6
Affiliations

Affiliations

  • 1 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America.
  • 2 Department of Food Science and Technology, Keimyung University, Daegu, Republic of Korea.
  • 3 Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, TX, United States of America.
  • 4 Department of Internal Medicine, Baylor College of Medicine, Houston, TX, United States of America.
  • 5 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America; Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, TX, United States of America.
  • 6 Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
PMID: 26035713 DOI: 10.1371/journal.pone.0128308
Abstract

The orphan nuclear receptor NR4A1 exhibits pro-oncogenic activity in Cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. Transfection of renal cell carcinoma (RCC) ACHN and 786-O cells with Oligonucleotides that target NR4A1 results in a 40-60% decrease in cell proliferation and induction of Apoptosis. Moreover, knockdown of NR4A1 in RCC cells decreased Bcl-2, Survivin and epidermal growth factor receptor expression, inhibited of mTOR signaling, induced oxidative and endoplasmic reticulum stress, and decreased TXNDC5 and IDH1. We have recently demonstrated that selected 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds including the p-hydroxyphenyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) analogs bind NR4A1 and act as antagonists. Both DIM-C-pPhOH and DIM-C-pPhCO2Me inhibited growth and induced Apoptosis in ACHN and 786-O cells, and the functional and genomic effects of the NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. These results indicate that NR4A1 antagonists target multiple growth promoting and pro-survival pathways in RCC cells and in tumors (xenograft) and represent a novel chemotherapy for treating RCC.

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