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

Erik Hedrick, Syng-Ook Lee, Gyungeun Kim, Maen Abdelrahim, Un-Ho Jin, Stephen H. Safe, Ala Abudayyeh

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)e0128308
JournalPLoS ONE
Volume10
Issue number6
DOIs
StatePublished - 2015

Keywords

  • Animals
  • Apoptosis
  • Blotting, Western
  • Carcinoma, Renal Cell
  • Cell Proliferation
  • Fluorescent Antibody Technique
  • Humans
  • Kidney Neoplasms
  • Male
  • Mice
  • Mice, Nude
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Oligonucleotides, Antisense
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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