Insulin-like growth factor binding protein-2 stimulates proliferation and activates multiple cascades of the mitogen-activated protein kinase pathways in NIH-OVCAR3 human epithelial ovarian cancer cells

Cancer Biol Ther. 2006 Feb;5(2):189-97. doi: 10.4161/cbt.5.2.2333. Epub 2006 Feb 15.

Abstract

Insulin-like growth factor binding protein-2 (IGFBP-2), the second most abundant IGFBP in the circulation, is dramatically increased in the serum and ovarian cyst fluid of women with epithelial ovarian cancer. The specific role of IGFBP-2 in ovarian carcinogenesis remains elusive. Using NIH-OVCAR3 human epithelial ovarian cancer cells, we have evaluated the effects of IGFBP-2 and its antibody on cell proliferation, activation of mitogen-activated protein kinase (MAP kinase) pathways and on cytokine expression. Treatment of the cells with IGFBP-2 stimulates cell growth significantly (p<.05) and potentiates the activation of (1) the extracellular signal regulated kinase (ERK1/2) signaling pathway, which transduces cell-specific growth and differentiation signals; (2) the stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK) pathway, which is activated by environmental stresses, inflammatory cytokines, growth factors and G-protein coupled receptor (GPCR) agonists; and (3) the p38 MAP kinase pathway, which mediates inflammatory and stress responses. Suppression of IGFBP-2, with its neutralizing antibody, significantly (p<.05) retards cell growth, blocks the activation of all three cascades of the MAPK pathways and downregulates the expression of a number of potential cancer-promoting cytokines. These novel findings may have important clinical implications for developing innovative strategies for the treatment and management of ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / enzymology*
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytokines / metabolism
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Insulin-Like Growth Factor Binding Protein 2 / antagonists & inhibitors*
  • Insulin-Like Growth Factor Binding Protein 2 / immunology
  • Insulin-Like Growth Factor Binding Protein 2 / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Ovarian Neoplasms / enzymology*
  • Phosphorylation / drug effects

Substances

  • Antibodies
  • Cytokines
  • Insulin-Like Growth Factor Binding Protein 2