Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells

Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18757-62. doi: 10.1073/pnas.0910218106. Epub 2009 Oct 21.

Abstract

There is strong evidence for a role of prostaglandin E(2) (PGE(2)) in cancer cell proliferation and tumor development. In PGE(2) biosynthesis, cyclooxygenases (COX-1/COX-2) convert arachidonic acid to PGH(2), which can be isomerized to PGE(2) by microsomal PGE-synthase-1 (MPGES-1). The human prostate cancer cell line DU145 expressed high amounts of MPGES-1 in a constitutive manner. MPGES-1 expression also was detectable in human prostate cancer tissues, where it appeared more abundant compared with benign hyperplasia. By using shRNA, we established stable and practically complete knockdown of MPGES-1, both in DU145 cells with high constitutive expression and in the non-small cell lung cancer cell line A549, where MPGES-1 is inducible. For microsomes prepared from knockdown clones, conversion of PGH(2) to PGE(2) was reduced by 85-90%. This resulted in clear phenotypic changes: MPGES-1 knockdown conferred decreased clonogenic capacity and slower growth of xenograft tumors (with disintegrated tissue structure) in nude mice. For DU145 cells, MPGES-1 knockdown gave increased apoptosis in response to genotoxic stress (adriamycin), which could be rescued by exogenous PGE(2). The results suggest that MPGES-1 is an alternative therapeutic target in cancer cells expressing this enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Clone Cells
  • Cyclooxygenase 2 / metabolism
  • Doxorubicin / pharmacology
  • Gene Knockdown Techniques
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors
  • Intramolecular Oxidoreductases / metabolism*
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Microsomes / drug effects
  • Microsomes / enzymology*
  • Prostaglandin-E Synthases
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / pathology*
  • Protein Transport / drug effects
  • Receptors, Androgen / metabolism
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / enzymology
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

Substances

  • Receptors, Androgen
  • Doxorubicin
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • Ptges protein, mouse