Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells
Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells
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DOI：
10.1097/00005537-200306000-00004
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发表时间：
2003-06-01
期刊：
影响因子：
2.6
通讯作者：
Pietenpol, JA
中科院分区：
文献类型：
--
作者：
Matheny, KE;Barbieri, CE;Pietenpol, JA
目标/假设。表皮生长因子受体（EGFR）和p53同源物p63在相当数量的头颈部鳞状细胞癌（HNSCC）中过表达。表皮生长因子受体和p63都具有致癌特性，包括增加细胞增殖和拮抗凋亡的潜力。ZD 1839（“易瑞沙”）是一种对EGFR酪氨酸激酶具有特异性的三磷酸腺苷竞争性抑制剂，目前正在评估其作为HNSCC中的化疗剂。目的是研究用ZD 1839处理HNSCC细胞后p63表达是否降低。ZD 1839下调p63将确定EGFR信号传导与p63之间的潜在分子关系，并可深入了解ZD 1839的作用机制。研究设计：ZD 1839处理后p63表达的体外检查。方法.用不同剂量的ZD 1839处理人HNSCC细胞系SCC-012。通过Western和北方印迹分析来分析p63蛋白和信使RNA水平。流式细胞仪分析ZD 1839对SCC-012细胞周期的影响。结果在SCC-012细胞中，在ZD 1839处理过程中，p63蛋白和信使RNA水平呈剂量依赖性降低。ZD 1839处理后磷酸化MAPK水平降低，p27（KIP-1）水平升高。ZD 1839处理诱导G1期细胞增加2倍，S期细胞减少3.5倍，与生长停滞一致。结论：ZD 1839在mRNA水平下调p63的表达，提示p63是EGFR信号转导的下游靶点。
Objective/Hypothesis. Both the epidermal growth factor receptor (EGFR) and the p53 homologue p63 are overexpressed in a significant number of cases of head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor and p63 both possess oncogenic properties, including the potential to increase cell proliferation and antagonize apoptosis. ZD1839 ("Iressa") is an adenosine triphosphate- competitive inhibitor specific to the EGFR tyrosine kinase currently under evaluation as a chemotherapeutic agent in HNSCC. The objective was to investigate whether p63 expression is decreased after treatment of HNSCC cells with ZD1839. Downregulation of p63 by ZD1839 would identify a potential molecular relationship between EGFR signaling and p63 and could provide insight into the mechanism of action of ZD1839. Study Design: In vitro examination of p63 expression after ZD1839 treatment. Methods. A human HNSCC cell line, SCC-012, was treated with varying doses of ZD1839. p63 protein and messenger RNA levels were analyzed by Western and Northern blot analyses. The effect of ZD1839 on SCC-012 cell cycle was analyzed by flow cytometric analysis. Results. In SCC-012 cells there was a dose-dependent decrease in p63 protein and messenger RNA levels over the course of ZD1839 treatment. Levels of phosphorylated MAPK decreased and p27(KIP-1) levels increased after ZD1839 treatment. ZD1839 treatment induced a twofold increase in G1-phase cells and a 3.5-fold decrease in S-phase cells consistent with growth arrest. Conclusion: ZD1839 downregulates p63 expression at the messenger RNA level, suggesting that p63 is a downstream target of EGFR signaling.