TGF-β Signaling Activation Confers Anlotinib Resistance in Gastric Cancer
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature..
BACKGROUND: Gastric cancer (GC) has always been a great threat to human health due to its aggressiveness and lethality. Anlotinib, a novel multi-target tyrosine kinase inhibitor (TKI), has been certified its anti-tumor effects on various tumors. Nonetheless, there are few studies on applying anlotinib as a treatment for GC. The underlying mechanism of acquired resistance during anlotinib administration remains unclear.
METHODS: We investigated the toxicologic effects of anlotinib on GC cells through CCK8, colony-forming, and flow cytometry assays in vitro and xenograft models in vivo. Anlotinib-resistant GC cells, AGS-R and MGC803-R, were generated and characterized by cell proliferation and apoptosis assays. The signaling pathways involved in anlotinib resistance were probed using Cignal™ Finder 10-Pathway Reporter Array. Western blot and dual-luciferase reporter assays were performed to confirm the relationships. The TGF-β inhibitor LY364947 was introduced to demonstrate the importance of TGF-β signaling in anlotinib resistance via a series of functional assays.
RESULTS: Anlotinib suppressed cell growth and induced apoptosis in vitro and inhibited tumorigenesis and metastasis in vivo, while its anti-tumor effects were impaired in anlotinib-resistant cells. The results of dual-luciferase reporter assays and western blot indicated TGF-β signaling was activated in anlotinib-resistant GC cells. LY364947 combined with Anlotinib exerted a better antineoplastic effect than monotherapy and considerably reversed the anlotinib resistance in GC.
CONCLUSIONS: Our findings suggested that TGF-β signaling may take a significant part in anlotinib resistance in GC. The suppression of TGF-β signaling may be a possible and promising approach for the GC oncotherapy when combined with anlotinib.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
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| Enthalten in: |
Pharmaceutical research - 40(2023), 3 vom: 21. März, Seite 689-699 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Jingde [VerfasserIn] |
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| Links: |
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| Themen: |
Anlotinib |
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| Anmerkungen: |
Date Completed 27.03.2023 Date Revised 27.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s11095-022-03461-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. | ||
| 520 | |a BACKGROUND: Gastric cancer (GC) has always been a great threat to human health due to its aggressiveness and lethality. Anlotinib, a novel multi-target tyrosine kinase inhibitor (TKI), has been certified its anti-tumor effects on various tumors. Nonetheless, there are few studies on applying anlotinib as a treatment for GC. The underlying mechanism of acquired resistance during anlotinib administration remains unclear | ||
| 520 | |a METHODS: We investigated the toxicologic effects of anlotinib on GC cells through CCK8, colony-forming, and flow cytometry assays in vitro and xenograft models in vivo. Anlotinib-resistant GC cells, AGS-R and MGC803-R, were generated and characterized by cell proliferation and apoptosis assays. The signaling pathways involved in anlotinib resistance were probed using Cignal™ Finder 10-Pathway Reporter Array. Western blot and dual-luciferase reporter assays were performed to confirm the relationships. The TGF-β inhibitor LY364947 was introduced to demonstrate the importance of TGF-β signaling in anlotinib resistance via a series of functional assays | ||
| 520 | |a RESULTS: Anlotinib suppressed cell growth and induced apoptosis in vitro and inhibited tumorigenesis and metastasis in vivo, while its anti-tumor effects were impaired in anlotinib-resistant cells. The results of dual-luciferase reporter assays and western blot indicated TGF-β signaling was activated in anlotinib-resistant GC cells. LY364947 combined with Anlotinib exerted a better antineoplastic effect than monotherapy and considerably reversed the anlotinib resistance in GC | ||
| 520 | |a CONCLUSIONS: Our findings suggested that TGF-β signaling may take a significant part in anlotinib resistance in GC. The suppression of TGF-β signaling may be a possible and promising approach for the GC oncotherapy when combined with anlotinib | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a TGF-β signaling | |
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| 700 | 1 | |a Hu, Qingqing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Xiaohua |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Yong |e verfasserin |4 aut | |
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