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

• Published in: PloS one 2015-06, Vol.10 (6), p.e0128308-e0128308
• Main Authors: Hedrick, Erik, Lee, Syng-Ook, Kim, Gyungeun, Abdelrahim, Maen, Jin, Un-Ho, Safe, Stephen, Abudayyeh, Ala
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Analogs; Animals; Antagonists; Apoptosis; Bcl-2 protein; Biology; Blotting, Western; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - therapy; Cell cycle; Cell growth; Cell Proliferation; Cell receptors; Cell survival; Chemotherapy; Drug targeting; Drug therapy; Endoplasmic reticulum; Epidermal growth factor; Fluorescent Antibody Technique; Gene expression; Genes; Genetic aspects; Health sciences; Humans; Immunoglobulins; Internal medicine; Isocitrate dehydrogenase; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidney Neoplasms - therapy; Kinases; Male; Medical prognosis; Medical research; Mice; Mice, Nude; Nuclear Receptor Subfamily 4, Group A, Member 1 - antagonists & inhibitors; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Oligonucleotides; Oligonucleotides, Antisense - genetics; Oxidative stress; Pharmacology; Physiological aspects; Physiology; Renal cell carcinoma; Signaling; Sp1 protein; Survival; Survivin; Thioredoxin; TOR protein; Transfection; Tumor cell lines; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128308

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.