Involvement of SNX1 in regulating EGFR endocytosis in a gefitinib-resistant NSCLC cell lines

Abstract

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.

Keywords

Lung cancer / drug-resistance / EGFR / endocytosis / endosomes/lysosomes / sorting nexin 1 / membrane recycling

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