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p21 expression is induced by activation of nuclear nerve growth factor-induced Balpha (Nur77) in pancreatic cancer

Syng-Ook Lee1, Sudhakar Chintharlapalli, Shengxi Liu

  • 1Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.

Molecular Cancer Research : MCR
|July 9, 2009
PubMed

Insights

The compound DIM-C-pPhOCH3 activates the Nur77 receptor, decreasing pancreatic cancer cell survival and inducing the p21 inhibitor. This novel pathway for p21 induction involves Sp proteins and the p21 promoter region.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The compound 1,1-Bis(3'-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) is known to activate the orphan receptor nerve growth factor-induced Balpha (Nur77).
  • Nur77 plays a role in cellular processes relevant to cancer, but its precise mechanisms of action in pancreatic cancer are not fully elucidated.

Purpose of the Study:

  • To investigate the effects of DIM-C-pPhOCH3 on pancreatic cancer cells, focusing on cell survival, cell cycle, and the induction of key regulatory proteins.
  • To elucidate the molecular mechanisms by which DIM-C-pPhOCH3 exerts its effects, particularly the role of Nur77 in regulating gene expression.

Main Methods:

  • Treatment of Panc1 pancreatic cancer cells with DIM-C-pPhOCH3.
  • Cell survival assays and cell cycle analysis (G0-G1 arrest).
  • Analysis of p21 and Krüppel-like factor 4 (KLF4) expression (mRNA and protein).
  • Reporter assays using p21 promoter constructs.
  • RNA interference studies targeting Nur77, Sp1, Sp3, and Sp4.
  • Chromatin immunoprecipitation (ChIP) assays.

Main Results:

  • DIM-C-pPhOCH3 decreased Panc1 cell survival and induced G0-G1 cell cycle arrest.
  • These effects were accompanied by the induction of cyclin-dependent kinase inhibitor p21, in a Nur77-dependent manner.
  • Nur77-dependent p21 induction required the GC-rich proximal region of the p21 promoter and involved interactions with Sp1 and Sp4, but not Sp3.
  • ChIP assays confirmed Nur77 interaction with the p21 promoter in treated cells.

Conclusions:

  • Activation of nuclear Nur77 by DIM-C-pPhOCH3 leads to a novel pathway for p21 induction in pancreatic cancer cells.
  • This pathway is independent of canonical Nur77 response elements but relies on Sp protein binding to the p21 promoter's GC-rich region.
  • These findings offer insights into potential therapeutic strategies targeting Nur77 and p21 in pancreatic cancer treatment.

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