Skin Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Skin Cancer, including details on identification, causes, prevention, treatment. | ||||||||
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c-Met is a potentially new therapeutic target for treatment of human melanoma.Puri N, Ahmed S, Janamanchi V, Tretiakova M, Zumba O, Krausz T, Jagadeeswaran R, Salgia R Departments of Hematology/Oncology and Pathology, University of Chicago Medical Center, Chicago, Illinois 60607, USA. 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. Published 3 April 2007 in Clin Cancer Res, 13(7): 2246-53.
© 2004-2008 Skin Cancer Research Today. All Rights Reserved. |
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