Malignant melanoma remains a disease where new therapies are needed. The type I IGF receptor (IGF-IR) has been shown to be involved in many aspects of melanoma cell biology. In this study, we first examined a series of human melanoma cell lines to investigate their response to IGF-I in cell signaling and motility. Some melanoma cells (WM35, WM 115 and WM 164) were poorly responsive to IGF-I stimulated signaling and cell motility, while others (WM1341D and WM1552C) were more responsive. We chose a non-responsive cell line (WM35) and two responsive cells lines (WM1341D and WM1552C) for further study. The non-responsive WM35 melanoma cells were unable to invade the extracellular matrix (ECM) composed of Matrigel. These cells also lacked IGF-IR and IRS adaptor proteins, which accounted for their absence of growth and motility response to IGF-I. In contrast, WM1341D melanoma cells responded to IGF-I with enhanced growth, motility and invasion. In these cells, IGF-I activated IGF-IR, IRS adaptor proteins, and the PI-3K signaling pathway. To disrupt IGF signaling, we used two strategies; IGF-IR was directly targeted by an inhibitory anti-IGF-IR antibody EM164 and IGF-I was neutralized by IGF binding protein-1 (IGFBP-1). EM164 (15μg/ml) and IGFBP-1 (80 nM) both blocked IGF-I stimulation of WM1341D growth and motility. IGF-I also stimulated invasion into a Matrigel matrix and a monolayer matrix of mesothelial or micro endothelial cells. Invasion in these model systems were blocked by EM164 and IGFBP-1. We have previously reported that IRS-2 affects human breast cancer cell motility. Since both WM1341D and WM1552C cells expressed IRS-2, we transfected these cells with IRS-2 siRNA to determine the effect on IGF-stimulated motility. Compared to Mock or non-transfected cells, the IRS-2 siRNA transfected cells had diminished IGF-mediated cell motility. These results provide further evidence of the effectiveness of anti IGF-IR strategy in experimental model systems of melanoma cell growth, migration and invasion. Thus, disruption of IGF signaling in malignant melanoma, either at the receptor or downstream adaptor level, represents a potential new therapeutic avenue for treatment of this disease.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]