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.
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.
Chakrabarty
Shilla
S
Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas 77555-1066, USA. schakrab@utmb.edu
Kondratick
Laura
L
D000230:Adenocarcinoma / Q000201:enzymology*; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects
D000906:Antibodies; D016207:Cytokines; D018971:Insulin-Like Growth Factor Binding Protein 2