吉非替尼
癌症研究
表皮生长因子受体
癌变
信号转导
蛋白激酶B
肺癌
表皮生长因子受体抑制剂
生物
化学
癌症
医学
细胞生物学
病理
内科学
作者
Shuai Shuai,Xin‐Hua Liao,Haixia Wang,Lusha Liu,Shiqi Mei,Jia-Xin Cao,Senming Wang
出处
期刊:Cancer Science
[Wiley]
日期:2021-08-10
卷期号:112 (10): 4139-4150
被引量:6
摘要
Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (eg, gefitinib) exert potent therapeutic efficacy in non–small‐cell lung cancer (NSCLC) harboring EGFR‐activating mutations. However, the resistance to EGFR TKIs limits their clinical therapeutic efficacy. TIP30, a newly identified tumor suppressor, appears to be involved in the regulation of cytoplasmic and nuclear EGFR signaling in NSCLC. Our previous study demonstrated that TIP30 regulated EGF‐dependent cyclin D1 transcription in human lung adenocarcinoma and suppressed tumorigenesis. In the present study, the involvement of TIP30 in combating gefitinib resistance in NSCLC was determined for the first time in vitro and in vivo. Gain and loss of function studies showed that overexpression of TIP30 effectively sensitized cells to gefitinib in vitro, whereas TIP30 inhibition promoted gefitinib cell resistance. Moreover, TIP30 negatively regulated the activation of the p‐AKT and p‐MEK signaling pathways in PC9/GR. Importantly, PC9/GR harbored high levels of nuclear EGFR, and overexpression of TIP30 restored irregular EGFR trafficking and degradation from early endosomes to the late endosomes, decreasing the nuclear accumulation of EGFR, which may partly or totally inhibit EGFR‐mediated induction of c‐ Myc transcription. Xenographic tumors induced by overexpression of TIP30 by PC9/GR cells in nude mice were suppressed compared with their original counterparts. Overall, it was revealed that TIP30 overexpression restored gefitinib sensitivity in NSCLC cells and attenuated the cytoplasmic and nuclear EGFR signaling pathways and may be a promising biomarker in gefitinib resistance in NSCLC.
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