title: Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma.
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.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Hedrick
authors.affiliation: Department of Food Science and Technology, Keimyung University, Daegu, Republic of Korea.
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, TX, United States of America.
authors.forename: Gyungeun
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Maen
authors.initials: M
authors.lastname: Abdelrahim
authors.affiliation: 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.
authors.forename: Un-Ho
authors.initials: UH
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Ala
authors.initials: A
authors.lastname: Abudayyeh
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016376:Oligonucleotides, Antisense