c-Met is a potentially new therapeutic target for treatment of human melanoma
c-Met is a potentially new therapeutic target for treatment of human melanoma
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DOI：
10.1158/1078-0432.ccr-06-0776
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发表时间：
2007-04-01
影响因子：
11.5
通讯作者：
Salgia, Ravi
中科院分区：
文献类型：
--
作者：
Puri, Neelu;Ahmed, Salman;Salgia, Ravi
目的：c-Met是一种受体酪氨酸激酶，参与细胞生长、侵袭、转移和血管生成。在这项研究中，我们研究了c-Met在黑色素瘤生物学中的作用，使用一种新的小分子酪氨酸激酶抑制剂SU 11274和小干扰（si）RNA对receptor.Experimental Design：SU 11274和c-Met siRNA的影响进行了研究，对增殖，凋亡，分化，活性氧和细胞内信号。c-Met突变进行了检查，c-Met和激活的c-Met的表达进行了研究，在痣，原发性和转移melanoma.Results：c-Met表达6：7黑色素瘤细胞系通过免疫印迹。SU 11274在所有黑色素瘤细胞系中抑制85%至98%的细胞生长，IC 50在1至2.5 μ mol/L之间，并在6种细胞系中的5种中引起凋亡（12-58%）。针对c-Met的siRNA抑制黑素瘤细胞的增殖达60%。这是第一个研究表明，SU 11274和siRNA诱导小白细胞相关转录因子（MITF）和其他几个黑色素瘤分化蛋白和形态分化的表型。SU 11274还抑制活性氧的形成和肝细胞生长因子对c-Met受体、AKT和S-6激酶的磷酸化。在细胞株和肿瘤组织中分别发现了c-Met跨膜区的一个新的错义突变N948 S和R988 C。c-Met在88%的黑色素瘤和15%的痣中表达，c-Met（pY 1003）在21%的人黑色素瘤中被激活。结论：c-Met在黑色素瘤的增殖、凋亡、分化和肿瘤进展中起重要作用。SU 11274可用于治疗性抑制黑色素瘤。
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 IC50 between 1 and 2.5 mu mol/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 microphthaImia-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.