Author(s): Puri N, Ahmed S, Janamanchi V, Tretiakova M, Zumba O,
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Abstract PURPOSE: c-Met is a receptor tyrosine kinase involved in cell growth, invasion, metastases, and angiogenesis. In this study, we investigated the role of c-Met in melanoma biology using a novel small-molecule tyrosine kinase inhibitor SU11274 and small interfering (si) RNA against the receptor. EXPERIMENTAL DESIGN: The effects of SU11274 and c-Met siRNA were studied on proliferation, apoptosis, differentiation, reactive oxygen species, and intracellular signaling. c-Met mutations were examined, and the expression of c-Met and activated c-Met was studied in nevi, primary, and metastatic melanoma. RESULTS: c-Met was expressed in 6:7 melanoma cell lines by immunoblotting. SU11274 inhibited cell growth in all melanoma cell lines by 85\% to 98\% with an IC(50) between 1 and 2.5 mumol/L and caused apoptosis (12-58\%) in five out of six cell lines. siRNA against c-Met inhibited proliferation of melanoma cells by 60\%. This is the first study that shows that SU11274 and siRNA induced microphthalmia-associated transcription factor (MITF) and several other melanoma differentiation proteins and a morphologically differentiated phenotype. SU11274 also inhibited reactive oxygen species formation and phosphorylation of c-Met receptor, AKT and S-6 kinase by the hepatocyte growth factor. A new missense c-Met mutation N948S was identified in cell lines and R988C in tumor tissue in the juxtamembrane domain of c-Met. It was found that c-Met was expressed in 88\% of melanomas and 15\% of nevi, and that c-Met (pY1003) was activated in 21\% of human melanomas. CONCLUSION: These results support the role of c-Met in proliferation, apoptosis, differentiation, and tumor progression of melanoma. SU11274 could be used in the therapeutic inhibition of melanoma.
This article was published in Clin Cancer Res
and referenced in Journal of Alzheimers Disease & Parkinsonism