Insulin-like growth factor I-stimulated melanoma cell migration requires phosphoinositide 3-kinase but not extracellular-regulated kinase activation.
Dysregulated signaling contributes to altered cellular growth, motility, and survival during cancer progression. We have evaluated the ability of several factors to stimulate migration in WM1341D, a cell line derived from an invasive human vertical growth phase melanoma. Basic fibroblast growth factor, hepatocyte growth factor, interleukin-8, and CCL27 each slightly increased migration. Insulin-like growth factor I (IGF-I), however, stimulated a 15-fold increase in migration. This response required the IGF-I receptor, which activates phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways. Both pathways have been implicated in migration in a variety of cell types, but the signaling required for IGF-I-induced melanoma cell migration is not well defined. IGF-I-stimulated activation of MAPK/ERK signaling in WM1341D cells was inhibited by U0126, but a 33-fold higher dose of U0126 was needed to inhibit IGF-I-stimulated cellular migration. In contrast, similar concentrations of either wortmannin or LY294002 were required to inhibit both IGF-I-induced PI3K activation and migration. These results indicate that IGF-I-stimulated migration of WM1341D cells requires PI3K activation but is independent of MAPK/ERK signaling. Determining the contributions of IGF-I signaling pathways to migration will help us to understand melanoma progression and may lead to new therapeutic targets of this highly metastatic cancer.
Department of Laboratory Medicine and Pathology, University of Minnesota, MMC 609, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Cheryl L
CL
Neudauer
James B
JB
McCarthy
D000818:Animals; D002465:Cell Movement; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases