兰州大学机构库 >基础医学院
YC-1 potentiates the antitumor activity of gefitinib by inhibiting HIF-1 alpha and promoting the endocytic trafficking and degradation of EGFR in gefitinib-resistant non-small-cell lung cancer cells
Hu, Hui1; Miao, XK(苗小康)2; Li, Jing-Yi1; Zhang, Xiao-Wei1; Xu, Jing-Jie1; Zhang, Jing-Ying2; Zhou, Tian-Xiong1; Hu, Ming-Ning1; Yang, Wen-Le2; Mou, LY(牟凌云)1
2020-05-05
Source PublicationEUROPEAN JOURNAL OF PHARMACOLOGY
ISSN0014-2999
Volume874
AbstractThe tyrosine kinase inhibitor (TKI) gefitinib exerts good therapeutic effect on NSCLC patients with sensitive EGFR-activating mutations. However, most patients ultimately relapse due to the development of drug resistance after 6-12 months of treatment. Here, we showed that a HIF-1 a inhibitor, YC-1, potentiated the antitumor efficacy of gefitinib by promoting EGFR degradation in a panel of human NSCLC cells with wild-type or mutant EGFRs. YC-1 alone had little effect on NSCLC cell survival but significantly enhanced the antigrowth and proapoptotic effects of gefitinib. In insensitive NSCLC cell lines, gefitinib efficiently inhibited the phosphorylation of EGFR but not the downstream signaling of ERK, AKT and STAT3; however, when combined with YC-1 treatment, these signaling pathways were strongly impaired. Gefitinib treatment induced EGFR arrest in the early endosome, and YC-1 treatment promoted delayed EGFR transport into the late endosome as well as receptor degradation. Moreover, the YC-1-induced reduction of HIF-1 alpha protein was associated with the enhancement of EGFR degradation. HIF-1 alpha knockdown promoted EGFR degradation, showing synergistic antigrowth and proapoptotic effects similar to those of the gefitinib and YC-1 combination treatment in NSCLC cells. Our findings provide a novel combination treatment strategy with gefitinib and YC-1 to extend the usage of gefitinib and overcome gefitinib resistance in NSCLC patients.
KeywordNSCLC Gefitinib YC-1 EGFR HIF-1 alpha Degradation
DOI10.1016/j.ejphar.2020.172961
Indexed BySCIE
Language英语
Funding ProjectNational Natural Science Foundation of China (NSFC)[81874315][81302798][21432003] ; Program for Chang-jiang Scholars and Innovative Research Team in University (PCSIRT)[IRT_15R27] ; Fundamental Research Funds for the Central Universities[lzujbky-2018-k9][lzujbky-2018-87]
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000519534200003
PublisherELSEVIER
Original Document TypeArticle
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.lzu.edu.cn/handle/262010/418835
Collection基础医学院
生命科学学院
Corresponding AuthorMou, Ling-Yun
Affiliation1.Lanzhou Univ, Inst Biochem & Mol Biol, Sch Life Sci, 222 TianShui South Rd, Lanzhou 730000, Peoples R China
2.Lanzhou Univ, Sch Basic Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China
First Author AffilicationSchool of Life Sciences
Corresponding Author AffilicationSchool of Life Sciences
Recommended Citation
GB/T 7714
Hu, Hui,Miao, Xiao-Kang,Li, Jing-Yi,et al. YC-1 potentiates the antitumor activity of gefitinib by inhibiting HIF-1 alpha and promoting the endocytic trafficking and degradation of EGFR in gefitinib-resistant non-small-cell lung cancer cells[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2020,874.
APA Hu, Hui.,Miao, Xiao-Kang.,Li, Jing-Yi.,Zhang, Xiao-Wei.,Xu, Jing-Jie.,...&Mou, Ling-Yun.(2020).YC-1 potentiates the antitumor activity of gefitinib by inhibiting HIF-1 alpha and promoting the endocytic trafficking and degradation of EGFR in gefitinib-resistant non-small-cell lung cancer cells.EUROPEAN JOURNAL OF PHARMACOLOGY,874.
MLA Hu, Hui,et al."YC-1 potentiates the antitumor activity of gefitinib by inhibiting HIF-1 alpha and promoting the endocytic trafficking and degradation of EGFR in gefitinib-resistant non-small-cell lung cancer cells".EUROPEAN JOURNAL OF PHARMACOLOGY 874(2020).
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