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

Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18567-71. doi: 10.1073/pnas.0509316102. Epub 2005 Dec 13.

Abstract

Activation of the Wnt/beta-catenin pathway promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents. Nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to antagonize beta-catenin function, but their mechanism of action is not known. We demonstrate here that interference with beta-catenin function by NSAIDs does not correlate with cyclooxygenase (COX) inhibition. Instead, NSAID inhibition of beta-catenin requires the high level expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and its co-receptor retinoid-X-receptor alpha (RXR-alpha). Immunoprecipitation experiments show that beta-catenin interacts with RXR-alpha and PPAR-gamma in some malignant cells. Repression of beta-catenin-dependent transcription by NSAIDs is thus indirect and depends on the coexpression of other nuclear receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Line, Tumor
  • Etodolac / pharmacology
  • Humans
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • PPAR gamma / metabolism
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Protein Binding
  • Retinoid X Receptors / metabolism
  • Signal Transduction / drug effects
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / metabolism*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • PPAR gamma
  • Retinoid X Receptors
  • beta Catenin
  • Etodolac
  • Prostaglandin-Endoperoxide Synthases