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Repression of beta-catenin function in malignant cells by nonsteroidal antiinflammatory drugs

Desheng Lu1, Howard B Cottam, Maripat Corr

  • 1Rebecca and John Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA. delu@ucsd.edu

Proceedings of the National Academy of Sciences of the United States of America
|December 15, 2005
PubMed

Insights

Nonsteroidal anti-inflammatory drugs (NSAIDs) target cancer by inhibiting the Wnt/beta-catenin pathway. This action depends on nuclear receptors peroxisome proliferator-activated receptor gamma (PPAR-gamma) and retinoid-X-receptor alpha (RXR-alpha), not cyclooxygenase (COX) inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The Wnt/beta-catenin pathway is crucial in cancer development.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to affect beta-catenin function.
  • The precise mechanism by which NSAIDs interfere with beta-catenin remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of NSAID interference with beta-catenin.
  • To investigate the role of cyclooxygenase (COX) inhibition versus other pathways.
  • To identify potential co-factors involved in NSAID-mediated beta-catenin repression.

Main Methods:

  • NSAID treatment of cancer cells.
  • Assessment of beta-catenin-dependent transcription.
  • Correlation analysis with cyclooxygenase (COX) inhibition.
  • Investigation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and retinoid-X-receptor alpha (RXR-alpha) expression.
  • Immunoprecipitation assays to detect protein interactions.

Main Results:

  • NSAID interference with beta-catenin function is independent of cyclooxygenase (COX) inhibition.
  • Inhibition requires high expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and retinoid-X-receptor alpha (RXR-alpha).
  • Beta-catenin directly interacts with RXR-alpha and PPAR-gamma in certain malignant cells.

Conclusions:

  • NSAIDs indirectly repress beta-catenin-dependent transcription.
  • This repression is contingent upon the co-expression of nuclear receptors PPAR-gamma and RXR-alpha.
  • NSAIDs represent a potential therapeutic strategy targeting the Wnt/beta-catenin pathway via nuclear receptor interactions in cancer.

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