Yang Zhibo, Bagheri-Yarmand Rozita, Wang Rui-An, Adam Liana, Papadimitrakopoulou Vali Vassiliki, Clayman Gary L, El-Naggar Adel, Lotan Reuben, Barnes Christopher J, Hong Waun Ki, Kumar Rakesh
Department of Molecular and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2004 Jan 15;10(2):658-67. doi: 10.1158/1078-0432.ccr-0382-03.
Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including those of the head and neck and breast. Accordingly, agents such as the EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (Iressa) are promising, biologically based treatments that are in various stages of preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival; this study explored the effect of ZD1839 on the stimulation of c-Src and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival of cancer cells.
We examined the effect of ZD1839 on biochemical and functional assays indicative of directional motility and cell survival, using human head and neck squamous cancer cells and breast cancer cells.
ZD1839 effectively inhibited c-Src activation and Pak1 activity in exponentially growing cancer cells. In addition, ZD1839 suppressed EGF-induced stimulation of EGFR autophosphorylation on Y1086 and Grb2-binding Y1068 sites, c-Src phosphorylation on Y215, and Pak1 activity. ZD1839 also blocked EGF-induced cytoskeleton remodeling, redistribution of activated EGFR, and in vitro invasiveness of cancer cells.
These studies suggest that the EGFR-TKI ZD1839 may cause potent inhibition of the Pak1 and c-Src pathways and, therefore, have potential to affect the invasiveness of human cancer cells deregulated in these growth factor receptor pathways.
表皮生长因子受体（EGFR）下游的表达和信号通路异常有助于人类癌症（包括头颈癌和乳腺癌）恶性表型的进展、侵袭和维持。因此，诸如EGFR酪氨酸激酶抑制剂（EGFR-TKI）ZD1839（易瑞沙）等药物是有前景的、基于生物学的治疗方法，正处于临床前和临床开发的各个阶段。肿瘤进展过程除其他步骤外，还需要增强转化、定向迁移和提高细胞存活率；本研究探讨了ZD1839对c-Src和p21激活激酶1（Pak1）的刺激作用，这两种激酶对癌细胞的转化、定向运动性和细胞存活至关重要。
我们使用人头颈鳞状癌细胞和乳腺癌细胞，研究了ZD1839对指示定向运动性和细胞存活的生化及功能测定的影响。
ZD1839有效抑制指数生长的癌细胞中的c-Src激活和Pak1活性。此外，ZD1839抑制EGF诱导的EGFR在Y1086位点的自磷酸化以及与Grb2结合的Y1068位点、Y215位点的c-Src磷酸化和Pak1活性。ZD1839还阻断了EGF诱导的细胞骨架重塑、活化EGFR的重新分布以及癌细胞的体外侵袭性。
这些研究表明，EGFR-TKI ZD1839可能会强力抑制Pak1和c-Src途径，因此有可能影响在这些生长因子受体途径中失调的人类癌细胞的侵袭性。
