Inactivation of the orphan nuclear receptor NR4A1 contributes to apoptosis induction by fangchinoline in pancreatic cancer cells

Hyo Seon Lee, Stephen Safe, Syng Ook Lee

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Previous studies have demonstrated that the orphan nuclear receptor NR4A1 is overexpressed in human pancreatic cancer and antagonizing this receptor promotes apoptosis and inhibits pancreatic cancer cells and tumor growth. In the present study, we identified fangchinoline, a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, as a new inactivator of nuclear NR4A1 and demonstrated that fangchinoline inhibits cell proliferation and induces apoptosis, in part, via the NR4A1-dependent pro-apoptotic pathways in human pancreatic cancer cells. It decreased expression of the antiapoptotic protein survivin by inhibiting Sp1-mediated transcription and induced oxidative stress-mediated endoplasmic reticulum (ER) stress in pancreatic cancer cells. These results suggest that inhibition of NR4A1-mediated transcriptional activity was involved in the anticancer effects of fangchinoline, and fangchinoline represents a novel class of mechanism-based anticancer agents targeting NR4A1 that is overexpressed in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)32-39
Number of pages8
JournalToxicology and Applied Pharmacology
Volume332
DOIs
StatePublished - Oct 1 2017
Externally publishedYes

Keywords

  • Apoptosis
  • ER stress
  • Fangchinoline
  • NR4A1
  • Pancreatic cancer
  • Sp1

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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