Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth

Syng Ook Lee, Maen Abdelrahim, Kyungsil Yoon, Sudhakar Chintharlapalli, Sabitha Papineni, Kyounghyun Kim, Huamin Wang, Stephen Safe

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

Activation of the orphan nuclear receptor TR3/Nur77 (NR4A1) promotes apoptosis and inhibits pancreatic tumor growth, but its endogenous function and the effects of its inactivation have yet to be determined. TR3 was overexpressed in human pancreatic tumors compared with nontumor tissue. Small interfering RNA-mediated knockdown of TR3 or cell treatment with the TR3 antagonist 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) decreased proliferation, induced apoptosis, and decreased expression of antiapoptotic genes including Bcl-2 and survivin in pancreatic cancer cells. Survivin suppression was mediated by formation of a TR3-Sp1-p300 DNA binding complex on the proximal GC-rich region of the survivin promoter. When administered in vivo, DIM-C-pPhOH induced apoptosis and inhibited tumor growth in an orthotopic model of pancreatic cancer, associated with inhibition of the same antiapoptotic markers observed in vitro. Our results offer preclinical validation of TR3 as a drug target for pancreatic cancer chemotherapy, based on the ability of TR3 inhibitors to block the growth of pancreatic tumors.

Original languageEnglish (US)
Pages (from-to)6824-6836
Number of pages13
JournalCancer research
Volume70
Issue number17
DOIs
StatePublished - Sep 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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