Inactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor Growth | Academic Article individual record

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.

author list (cited authors)
Lee, S., Abdelrahim, M., Yoon, K., Chintharlapalli, S., Papineni, S., Kim, K., Wang, H., & Safe, S.
publication date
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  • Male
  • RNA, Small Interfering
  • Sp1 Transcription Factor
  • Cell Line, Tumor
  • Cell Growth Processes
  • Humans
  • Apoptosis
  • Mice, Nude
  • Microtubule-Associated Proteins
  • Inhibitor Of Apoptosis Proteins
  • Pancreatic Neoplasms
  • Xenograft Model Antitumor Assays
  • Indoles
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Transfection
  • Gene Knockdown Techniques
  • Anisoles
  • E1a-associated P300 Protein
  • Animals
  • Mice
  • Phenols
  • Survivin
  • Transcriptional Activation