| 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 Publication | EUROPEAN JOURNAL OF PHARMACOLOGY
 |
| ISSN | 0014-2999 |
| Volume | 874 |
| Abstract | The 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. |
| Keyword | NSCLC Gefitinib YC-1 EGFR HIF-1 alpha Degradation |
| DOI | 10.1016/j.ejphar.2020.172961 |
| Indexed By | SCIE |
| Language | 英语 |
| Funding Project | National 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 Area | Pharmacology & Pharmacy |
| WOS Subject | Pharmacology & Pharmacy |
| WOS ID | WOS:000519534200003 |
| Publisher | ELSEVIER |
| Original Document Type | Article |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.lzu.edu.cn/handle/262010/418835 |
| Collection | 基础医学院 生命科学学院 |
| Corresponding Author | Mou, Ling-Yun |
| Affiliation | 1.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 Affilication | School of Life Sciences |
| Corresponding Author Affilication | School 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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