Targeting MET endocytosis or degradation to overcome HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma
Copyright © 2023 Elsevier Inc. All rights reserved..
The overexpression of hepatic growth factor(HGF) is one of the important reasons for the development of gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma cells. Targeting the HGF receptor MET through endocytosis inhibition or degradation induction has been proposed as a potential strategy to overcome this resistance. However, the effectiveness of this approach remains needs to be evaluated. In this study, we observed that MET receptors undergo persistent endocytosis but rarely enter the degradation pathway in HGF-overexpressing cells. We showed that MET endocytosis can be inhibited by using gene silence method or MET inhibitors. CHC or DNM2 gene silence slightly increases the sensitivity of resistant cells to gefitinib without affecting MET activity, while GRB2 gene silence can simultaneously inhibit MET endocytosis and reduce MET activity, resulting in a significant reversal effect of gefitinib resistance. Similarly, MET inhibitors significantly reverse drug resistance, accompanied by simultaneous inhibition of MET endocytosis and activity, highlighting the importance of both endocytosis and activity in HGF-induced gefitinib resistance. Additionally, we demonstrated that promoting MET degradation through deubiquitinase (USP8 or USP32) gene silence is another effective method for reversing drug resistance. Overall, our findings suggest that targeting MET receptor endocytosis and degradation is an attractive strategy for overcoming HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:682 |
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| Enthalten in: |
Biochemical and biophysical research communications - 682(2023) vom: 19. Nov., Seite 371-380 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jiao, Demin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.11.2023 Date Revised 05.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbrc.2023.10.037 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363372156 |
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| 245 | 1 | 0 | |a Targeting MET endocytosis or degradation to overcome HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma |
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| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a The overexpression of hepatic growth factor(HGF) is one of the important reasons for the development of gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma cells. Targeting the HGF receptor MET through endocytosis inhibition or degradation induction has been proposed as a potential strategy to overcome this resistance. However, the effectiveness of this approach remains needs to be evaluated. In this study, we observed that MET receptors undergo persistent endocytosis but rarely enter the degradation pathway in HGF-overexpressing cells. We showed that MET endocytosis can be inhibited by using gene silence method or MET inhibitors. CHC or DNM2 gene silence slightly increases the sensitivity of resistant cells to gefitinib without affecting MET activity, while GRB2 gene silence can simultaneously inhibit MET endocytosis and reduce MET activity, resulting in a significant reversal effect of gefitinib resistance. Similarly, MET inhibitors significantly reverse drug resistance, accompanied by simultaneous inhibition of MET endocytosis and activity, highlighting the importance of both endocytosis and activity in HGF-induced gefitinib resistance. Additionally, we demonstrated that promoting MET degradation through deubiquitinase (USP8 or USP32) gene silence is another effective method for reversing drug resistance. Overall, our findings suggest that targeting MET receptor endocytosis and degradation is an attractive strategy for overcoming HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Degradation | |
| 650 | 4 | |a Endocytosis | |
| 650 | 4 | |a Gefitinib resistance | |
| 650 | 4 | |a Lung adenocarcinoma | |
| 650 | 4 | |a MET | |
| 650 | 7 | |a Gefitinib |2 NLM | |
| 650 | 7 | |a S65743JHBS |2 NLM | |
| 650 | 7 | |a Quinazolines |2 NLM | |
| 650 | 7 | |a ErbB Receptors |2 NLM | |
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| 650 | 7 | |a Hepatocyte Growth Factor |2 NLM | |
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| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a HGF protein, human |2 NLM | |
| 650 | 7 | |a EGFR protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 700 | 1 | |a Chen, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Xiali |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yongyang |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Chunyan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Qingyong |e verfasserin |4 aut | |
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