Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta

Cancer Cell. 2004 Sep;6(3):285-95. doi: 10.1016/j.ccr.2004.08.011.

Abstract

Cyclooxygenase-derived prostaglandin E(2) (PGE(2)) is the predominant prostanoid found in most colorectal cancers (CRC) and is known to promote colon carcinoma growth and invasion. However, the key downstream signaling pathways necessary for PGE(2)-induced intestinal carcinogenesis are unclear. Here we report that PGE(2) indirectly transactivates PPARdelta through PI3K/Akt signaling, which promotes cell survival and intestinal adenoma formation. We also found that PGE(2) treatment of Apc(min) mice dramatically increased intestinal adenoma burden, which was negated in Apc(min) mice lacking PPARdelta. We demonstrate that PPARdelta is a focal point of crosstalk between the prostaglandin and Wnt signaling pathways which results in a shift from cell death to cell survival, leading to increased tumor growth.

Publication types

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

MeSH terms

  • Adenoma / metabolism*
  • Animals
  • Cell Survival
  • Chromones / pharmacology
  • Colorectal Neoplasms / metabolism*
  • Dinoprostone / metabolism*
  • Dinoprostone / pharmacology
  • Genes, APC
  • Humans
  • Male
  • Mice
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcription Factors / metabolism*
  • Transcriptional Activation*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Chromones
  • Morpholines
  • Proto-Oncogene Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Dinoprostone