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PLoS One. 2015 Jun 2;10(6):e0128308. doi: 10.1371/journal.pone.0128308. eCollection 2015.

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

Author information

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.

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.

PMID:
26035713
PMCID:
PMC4452731
DOI:
10.1371/journal.pone.0128308
[Indexed for MEDLINE]
Free PMC Article

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