Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis

Ying Hu, Thinh Chau, Hui Xin Liu, Degui Liao, Ryan Keane, Yuqiang Nie, Hui Yang, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Bile acids (BA) are endogenous agents capable of causing cancer throughout the gastrointestinal (GI) tract. To uncover the mechanism by which BAs exert carcinogenic effects, both human liver and colon cancer cells as well as mouse primary hepatocytes were treated with BAs and assayed for viability, genotoxic stress, and transcriptional response. BAs induced both Nur77 (NR4A1) and proinflammatory gene expression. The intracellular location of BA-induced Nur77 was time dependent; short-term (1-3 hours) exposure induced nuclear Nur77, whereas longer (1-2 days) exposure also increased cytosolic Nur77 expression and apoptosis. Inhibiting Nur77 nuclear export with leptomycin B decreased lithocholic acid (LCA)-induced apoptosis. Extended (7 days) treatment with BA generated resistance to BA with increased nuclear Nur77, viability, and mobility. While, knockdown of Nur77 in BA-resistant cells increased cellular susceptibility to LCA-induced apoptosis. Moreover, in vivo mouse xenograft experiments demonstrated that BA-resistant cells form larger tumors with elevated Nur77 expression compared with parental controls. DNA-binding and gene expression assays identified multiple survival genes (CDK4, CCND2, MAP4K5, STAT5A, and RBBP8) and a proapoptosis gene (BID) as Nur77 targets. Consistently, BA-induced upregulation of the aforementioned genes was abrogated by a lack of Nur77. Importantly, Nur77 was overexpressed in high percentage of human colon and liver cancer specimens, and the intracellular location of Nur77 correlated with elevated serum total BA levels in patients with colon cancer. These data show for the first time that BAs via Nur77 have a dual role in modulating cell survival and death. Implications: These findings establish a direct link between Nur77 and the carcinogenic effect of BAs.

Original languageEnglish (US)
Pages (from-to)281-292
Number of pages12
JournalMolecular Cancer Research
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis'. Together they form a unique fingerprint.

Cite this