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Anti-growth and pro-apoptotic effects of dasatinib on human oral cancer cells through multi-targeted mechanisms

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Author(s)
Nam-Sook ParkYu-Kyung ParkAnil Kumar YadavYoung-Min ShinDavid Bishop-BaileyJong-Soon ChoiJong Wook ParkByeong-Churl Jang
Keimyung Author(s)
Shin, Young MinPark, Jong WookJang, Byeong Churl
Department
Dept. of Dentistry (치과학)
Dept. of Immunology (면역학)
Dept. of Molecular Medicine (분자의학)
Journal Title
J Cell Mol Med
Issued Date
2021
Volume
25
Issue
17
Keyword
apoptosisdasatinibHIF-1αHSC-3SrcYD-38
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.
Keimyung Author(s)(Kor)
신영민
박종욱
장병철
Publisher
School of Medicine (의과대학)
Citation
Nam-Sook Park et al. (2021). Anti-growth and pro-apoptotic effects of dasatinib on human oral cancer cells through multi-targeted mechanisms. J Cell Mol Med, 25(17), 8300–8311. doi: 10.1111/jcmm.16782
Type
Article
ISSN
1582-4934
Source
https://onlinelibrary.wiley.com/doi/10.1111/jcmm.16782
DOI
10.1111/jcmm.16782
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/43960
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Dentistry (치과학)
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
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