Anti-growth and pro-apoptotic effects of dasatinib on human oral cancer cells through multi-targeted mechanisms |
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Authors: | Nam-Sook Park Yu-Kyung Park Anil Kumar Yadav Young-Min Shin David Bishop-Bailey Jong-Soon Choi Jong Wook Park Byeong-Churl Jang |
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Institution: | 1. Department of Molecular Medicine, College of Medicine, Keimyung University, Daegu, Korea
Contribution: ?Investigation (equal), Methodology (equal);2. Department of Molecular Medicine, College of Medicine, Keimyung University, Daegu, Korea;3. Department of Molecular Medicine, College of Medicine, Keimyung University, Daegu, Korea
Contribution: Data curation (equal), ?Investigation (equal), Writing - original draft (equal);4. Department of Dentistry, College of Medicine, Keimyung University, Daegu, Korea
Contribution: Formal analysis (equal), Validation (equal);5. North Cornwall Research Institute, Cornwall, UK;6. Biological Disaster Analysis Group, Division of Convergence Biotechnology, Korea Basic Science Institute, Daejeon, Korea;7. Department of Immunology, College of Medicine, Keimyung University, Daegu, Korea |
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Abstract: | 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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Keywords: | apoptosis dasatinib HIF-1α HSC-3 Src YD-38 |
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