EGFR inhibitor-driven endoplasmic reticulum stress-mediated injury on intestinal epithelial cells
EGFR inhibitor-driven endoplasmic reticulum stress-mediated injury on intestinal epithelial cells
复制标题
EGFR抑制剂驱动的内质网应激介导的肠上皮细胞损伤
DOI：
10.1016/j.lfs.2014.10.008
复制
发表时间：
2014-12-05
期刊：
影响因子：
6.1
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Hong, Shaocheng;Gu, Yanhong;Xu, Qiang
Aims: The aim of this study is to understand the underlying mechanisms regulating the adverse effect of diarrhea caused by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).Main methods: We comparatively examined the effects of two EGFR-TKIs, gefitinib and icotinib, on intestinal epithelial cells (IEC-6). Cell proliferation was measured using MTT analysis. Expression of multiple cytokines was assayed by real-time PCR. Cell cycle and apoptosis of IEC were evaluated using flow cytometry. Protein levels were determined by Western blot.Key findings: These two EGFR-TKIs exerted cytotoxicity to inhibit proliferation and induce apoptosis in IEC-6 cells. These effects are due to the ability of these EGFR-TKIs to cause cell cycle arrest at G0/G1 by regulating the expression of cyclin D1 and p27. In addition, gefitinib and icotinib significantly suppressed the levels of cell adhesion molecules while increasing the expression of the proinflammatory cytokines interleukin (IL)-6 and IL-25. Finally, these EGFR-TKIs triggered an endoplasmic reticulum (ER) stress response, characterized by the activation of the RNA dependent protein kinase-like ER kinase (PERK) pathway and the transcriptional induction of XBP-1 signaling, resulting in ER-mediated cell death. Moreover, gefitinib exerted more cytotoxicity than icotinib on IEC-6 cells.Significance: Because diarrhea is a common adverse event occurring in patients receiving small-molecular EGFR-TKI chemotherapy, the results of this study are clinically significant. The finding that icotinib exerts less cytotoxic activity than gefitinib on IEC-6 cells indicates its usefulness as a less toxic treatment option for non-small-cell lung cancer. (C) 2014 Elsevier Inc. All rights reserved.
