Combined inhibition of PLC{gamma}-1 and c-Src abrogates epidermal growth factor receptor-mediated head and neck squamous cell carcinoma invasion.
Combined inhibition of PLC{gamma}-1 and c-Src abrogates epidermal growth factor receptor-mediated head and neck squamous cell carcinoma invasion.
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DOI：
10.1158/1078-0432.ccr-07-4857
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发表时间：
2008-07-01
期刊：
影响因子：
--
通讯作者：
Thomas SM
中科院分区：
文献类型：
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作者：
Nozawa H;Howell G;Suzuki S;Zhang Q;Qi Y;Klein-Seetharaman J;Wells A;Grandis JR;Thomas SM
头颈部鳞状细胞癌（HNSCC）的死亡率通常与肿瘤局部浸润到重要器官（包括气道）有关。了解消除HNSCC侵袭的信号机制可能会揭示新的干预治疗靶点。本研究旨在探讨联合抑制c-Src和PLCγ-1对头颈部鳞状细胞癌（HNSCC）侵袭能力的影响。PLCγ-1和c-Src的抑制是通过小分子抑制剂和显性负性方法的组合来实现的。采用Matrigel包被的transwell体外侵袭实验检测PLCγ-1和c-Src对HNSCC细胞侵袭能力的影响。此外，利用免疫沉淀反应和计算机数据挖掘技术研究了PLCγ-1与c-Src的相互作用。在此，我们证明用PLC抑制剂U 73122或Src家族抑制剂AZD 0530抑制PLCγ-1或c-Src，或使用显性阴性构建体减弱EGF刺激的HNSCC侵袭。此外，EGF刺激增加了HNSCC细胞中PLCγ-1和c-Src之间的关联。联合抑制PLCγ-1和c-Src可进一步减弱HNSCC细胞的体外侵袭能力。这些累积的结果表明PLCγ-1和c-Src激活有助于EGFR下游的HNSCC侵袭，靶向这些通路可能是预防HNSCC中肿瘤侵袭的新策略。
Mortality from head and neck squamous cell carcinoma (HNSCC) is usually associated with locoregional invasion of the tumor into vital organs including the airway. Understanding the signaling mechanisms that abrogate HNSCC invasion may reveal novel therapeutic targets for intervention. The purpose of this study was to investigate the efficacy of combined inhibition of c-Src and PLCγ-1 in the abrogation of head and neck squamous cell carcinoma (HNSCC) invasion. PLCγ-1 and c-Src inhibition was achieved by a combination of small molecule inhibitors and dominant negative approaches. The effect of inhibition of PLCγ-1 and c-Src on invasion of HNSCC cells was assessed in an in vitro Matrigel coated transwell invasion assay. In addition, the immunoprecipitation reactions and in silico database mining was used to examine the interactions between PLCγ-1 and c-Src. Here we demonstrate that Inhibition of PLCγ-1 or c-Src with the PLC inhibitor U73122 or the Src family inhibitor AZD0530, or using dominant-negative constructs attenuated EGF-stimulated HNSCC invasion. Further, EGF stimulation increased the association between PLCγ-1 and c-Src in HNSCC cells. Combined inhibition of PLCγ-1 and c-Src resulted in further attenuation of HNSCC cell invasion in vitro. These cumulative results suggest that PLCγ-1 and c-Src activation contribute to HNSCC invasion downstream of EGFR and that targeting these pathways may be a novel strategy to prevent tumor invasion in HNSCC.