药物吉非替尼,EGFR酪氨酸激酶的特异性抑制剂,已被证明可以抑制EGFR信号的激活,从而在非小细胞肺癌细胞系中存活和细胞增殖。多年来,EGFR胞吞作用已作为研究配体诱导的模型,受体介导的内吞作用。在EGF刺激下,EGFR通过网格蛋白包被的囊泡内化并转运至早期内体,然后EGFR募集和磷酸化信号分子,导致下游信号如MAPK/PI3K/AKT通路的激活-这是调节细胞生长的重要机制。一旦被送到溶酶体,EGFR被降解以通过胞吞作用终止细胞内EGFR信号传导;该过程被称为受体下调。因此,EGFR的内吞作用与细胞内EGFR信号的减弱密切相关。或者,EGFR从早期内体返回到细胞表面用于持续的信号传导。以前的报告显示,在吉非替尼敏感的NSCLC细胞系中,有能力的EGF诱导的EGFR内吞作用及其快速下调有效进行。相比之下,吉非替尼耐药细胞系显示EGFR内吞作用受损,内化的EGFR在早期内体聚集,与过表达的排序Nexin1(SNX1)相关,最初被鉴定为与EGFR相互作用的蛋白质。因此,EGFR内吞失调与吉非替尼耐药有关,因为它导致不受控制的信号转导。目前,EGFR内吞与肺癌耐药的治疗相关性尚未明确.本文就吉非替尼耐药肺癌细胞中与SNX1转运相关的EGFR内吞作用机制进行综述。
The drug gefitinib, a specific inhibitor of EGFR tyrosine kinase, has been shown to suppress the activation of EGFR signaling for survival and cell proliferation in non-small cell lung cancer cell lines. For many years, EGFR endocytosis has served as a model for investigating ligand-induced, receptor-mediated endocytosis. On EGF stimulation, EGFR is internalized and transported via clathrin-coated vesicles to early endosomes, and EGFR then recruits and phosphorylates signaling molecules, leading to the activation of downstream signaling such as MAPK/PI3K/AKT pathways-an important mechanism for regulating cell growth. Once delivered to the lysosomes, EGFR is degraded to terminate intracellular EGFR signaling via endocytosis; this process is known as receptor downregulation. Therefore, the endocytosis of EGFR is closely related with attenuation of intracellular EGFR signaling. Alternatively, EGFR is returned to cell surface from early endosomes for the continued signaling. Previous reports revealed that a competent EGF-induced endocytosis of EGFR followed by its rapid downregulation efficiently proceeds in the gefitinib-sensitive NSCLC cell lines. In contrast, gefitinib-resistant cell lines showed that EGFR endocytosis is impaired and the internalized EGFR is aggregated in the early endosomes, which is associated with the overexpressed sorting nexin 1 (SNX1), initially identified as a protein that interacts with EGFR. Thus dysregulated EGFR endocytosis is implicated in gefitinib resistance, as it leads to uncontrolled signal transduction. At present, the therapeutic relevance of EGFR endocytosis with regard to drug resistance in lung cancer has not been clarified. This review focused on the mechanism for EGFR endocytosis associated with SNX1 trafficking in gefitinib-resistant lung cancer cells.