Anti-growth and pro-apoptotic effects of dasatinib on human oral cancer cells through multi-targeted mechanisms
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd..
Dasatinib is an inhibitor of Src that has anti-tumour effects on many haematological and solid cancers. However, the anti-tumour effects of dasatinib on human oral cancers remain unclear. In this study, we investigated the effects of dasatinib on different types of human oral cancer cells: the non-tumorigenic YD-8 and YD-38 and the tumorigenic YD-10B and HSC-3 cells. Strikingly, dasatinib at 10 µM strongly suppressed the growth and induced apoptosis of YD-38 cells and inhibited the phosphorylation of Src, EGFR, STAT-3, STAT-5, PKB and ERK-1/2. In contrast, knockdown of Src blocked the phosphorylation of EGFR, STAT-5, PKB and ERK-1/2, but not STAT-3, in YD-38 cells. Dasatinib induced activation of the intrinsic caspase pathway, which was inhibited by z-VAD-fmk, a pan-caspase inhibitor. Dasatinib also decreased Mcl-1 expression and S6 phosphorylation while increased GRP78 expression and eIF-2α phosphorylation in YD-38 cells. In addition, to its direct effects on YD-38 cells, dasatinib also exhibited anti-angiogenic properties. Dasatinib-treated YD-38 or HUVEC showed reduced HIF-1α expression and stability. Dasatinib alone or conditioned media from dasatinib-treated YD-38 cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Importantly, dasatinib's anti-growth, anti-angiogenic and pro-apoptotic effects were additionally seen in tumorigenic HSC-3 cells. Together, these results demonstrate that dasatinib has strong anti-growth, anti-angiogenic and pro-apoptotic effects on human oral cancer cells, which are mediated through the regulation of multiple targets, including Src, EGFR, STAT-3, STAT-5, PKB, ERK-1/2, S6, eIF-2α, GRP78, caspase-9/3, Mcl-1 and HIF-1α.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Journal of cellular and molecular medicine - 25(2021), 17 vom: 14. Sept., Seite 8300-8311 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Park, Nam-Sook [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 14.02.2022 Date Revised 07.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/jcmm.16782 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM328632945 |
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| 245 | 1 | 0 | |a Anti-growth and pro-apoptotic effects of dasatinib on human oral cancer cells through multi-targeted mechanisms |
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| 520 | |a © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. | ||
| 520 | |a Dasatinib is an inhibitor of Src that has anti-tumour effects on many haematological and solid cancers. However, the anti-tumour effects of dasatinib on human oral cancers remain unclear. In this study, we investigated the effects of dasatinib on different types of human oral cancer cells: the non-tumorigenic YD-8 and YD-38 and the tumorigenic YD-10B and HSC-3 cells. Strikingly, dasatinib at 10 µM strongly suppressed the growth and induced apoptosis of YD-38 cells and inhibited the phosphorylation of Src, EGFR, STAT-3, STAT-5, PKB and ERK-1/2. In contrast, knockdown of Src blocked the phosphorylation of EGFR, STAT-5, PKB and ERK-1/2, but not STAT-3, in YD-38 cells. Dasatinib induced activation of the intrinsic caspase pathway, which was inhibited by z-VAD-fmk, a pan-caspase inhibitor. Dasatinib also decreased Mcl-1 expression and S6 phosphorylation while increased GRP78 expression and eIF-2α phosphorylation in YD-38 cells. In addition, to its direct effects on YD-38 cells, dasatinib also exhibited anti-angiogenic properties. Dasatinib-treated YD-38 or HUVEC showed reduced HIF-1α expression and stability. Dasatinib alone or conditioned media from dasatinib-treated YD-38 cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Importantly, dasatinib's anti-growth, anti-angiogenic and pro-apoptotic effects were additionally seen in tumorigenic HSC-3 cells. Together, these results demonstrate that dasatinib has strong anti-growth, anti-angiogenic and pro-apoptotic effects on human oral cancer cells, which are mediated through the regulation of multiple targets, including Src, EGFR, STAT-3, STAT-5, PKB, ERK-1/2, S6, eIF-2α, GRP78, caspase-9/3, Mcl-1 and HIF-1α | ||
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| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
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| 700 | 1 | |a Yadav, Anil Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Young-Min |e verfasserin |4 aut | |
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| 700 | 1 | |a Choi, Jong-Soon |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Jong Wook |e verfasserin |4 aut | |
| 700 | 1 | |a Jang, Byeong-Churl |e verfasserin |4 aut | |
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