Anti‐growth and pro‐apoptotic effects of dasatinib on human oral cancer cells through multi‐targeted mechanisms
| Autor: | Jong-Soon Choi, Nam-Sook Park, Anil Kumar Yadav, David Bishop-Bailey, Jong-Wook Park, Yu-Kyung Park, Youngmin Shin, Byeong-Churl Jang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Dasatinib
Antineoplastic Agents YD‐38 hemic and lymphatic diseases Cell Line Tumor medicine Biomarkers Tumor Humans HSC‐3 Protein Kinase Inhibitors Tube formation Matrigel Gene knockdown Chemistry HIF‐1α apoptosis Cell Biology Original Articles Apoptosis Cancer cell Cancer research Carcinoma Squamous Cell Molecular Medicine Phosphorylation Original Article Mouth Neoplasms medicine.drug Proto-oncogene tyrosine-protein kinase Src Src |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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