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

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 (a) the extracellular signal regulated kinases (ERK1/2) signaling pathway, which transduces cell-specific growth and differentiation signals; (b) 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 (c) 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.