Cyclooxygenase-2 modulates the insulin-like growth factor axis in non-small-cell lung cancer

Cancer Res. 2004 Sep 15;64(18):6549-55. doi: 10.1158/0008-5472.CAN-04-1225.

Abstract

Constitutive overexpression of cyclooxygenase-2 (COX-2) occurs frequently in several different malignancies, including lung, colon, breast, and prostate cancer. Clinical studies have established elevated serum insulin-like growth factor (IGF-I) content and IGF-I:IGF-binding protein 3 (IGFBP-3) ratio as risk factors for these same malignancies. Therefore, we sought to determine the link between COX-2 expression and the IGF axis in COX-2 gene-modified human non-small-cell lung cancer (NSCLC) cells. Overexpression of COX-2 in NSCLC cells enhanced the antiapoptotic and mitogenic effects of IGF-I and IGF-II, facilitated the autophosphorylation of the type 1 IGF receptor, increased class IA phosphatidylinositol 3'-kinase activity, and decreased expression of IGFBP-3. Thus, these findings show that COX-2 augments the stimulatory arm of the IGF axis.

Publication types

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

MeSH terms

  • Apoptosis / physiology
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Celecoxib
  • Cell Division / physiology
  • Cell Line, Tumor
  • Cell Survival / physiology
  • Cyclooxygenase 2
  • DNA, Antisense / genetics
  • Down-Regulation / drug effects
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / biosynthesis
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Insulin-Like Growth Factor II / pharmacology
  • Insulin-Like Growth Factor II / physiology*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Isoenzymes / physiology*
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Membrane Proteins
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / physiology*
  • Pyrazoles
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / physiology
  • Sulfonamides / pharmacology

Substances

  • DNA, Antisense
  • Insulin-Like Growth Factor Binding Protein 3
  • Isoenzymes
  • Membrane Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrazoles
  • Sulfonamides
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Receptor, IGF Type 1
  • Celecoxib