Targeting c-MET by Tivantinib through synergistic activation of JNK/c-jun pathway in cholangiocarcinoma
Clinical treatment options for human cholangiocarcinoma (CC) are limited. c-MET, a high-affinity receptor for hepatocyte growth factor (HGF), is deregulated in many cancers. Its role in cholangiocarcinogenesis remains unclear. In current study, 23 corresponding tumor- and non-tumor tissues, taken fr...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
[2019]
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| In: |
Cell death & disease
Year: 2019, Jahrgang: 10, Heft: 3 |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-019-1460-1 |
| Online-Zugang: | Verlag, Volltext: https://doi.org/10.1038/s41419-019-1460-1 Verlag, Volltext: https://www.nature.com/articles/s41419-019-1460-1 
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| Verfasserangaben: | Kai Wei, Mao Li, Margot Zöller, Meng Wang, Arianeb Mehrabi and Katrin Hoffmann |
| Zusammenfassung: | Clinical treatment options for human cholangiocarcinoma (CC) are limited. c-MET, a high-affinity receptor for hepatocyte growth factor (HGF), is deregulated in many cancers. Its role in cholangiocarcinogenesis remains unclear. In current study, 23 corresponding tumor- and non-tumor tissues, taken from patients with intrahepatic (iCC) and perihilar cholangiocarcinoma (pCC), who underwent liver resection, were analyzed. The relationship of clinicopathological features and c-MET, as well as c-jun N-terminal kinase (JNK) was evaluated. The anti-tumor effects of Tivantinib, a small-molecule inhibitor with potent activity against the c-MET kinase, was investigated in three human CC cell lines, namely HUCC-T1, TFK-1, and EGI-1. In comparison with the results obtained in non-tumor tissue samples, c-MET was overexpressed in 91.3 % of tumor tissues (p < 0.01). The JNK expression was higher in tumor tissue compared with the corresponding non-tumor tissue sample in 17.4% patients (p < 0.01). The inhibition of aberrant c-MET expression in human CC cell lines was achieved by blocking the phosphorylation of c-MET with Tivantinib. Notable losses in cell viability and colony-forming capability were detected (p < 0.01). Synergistic activation of the JNK/c-jun pathway was demonstrated after Tivantinib treatment. Knockdown of the JNK by siRNA or competitive binding of c-MET receptor by stimulation with HGF-antagonized anti-tumor effects of Tivantinib was observed. Our data suggest that inhibition of c-MET could be a possible alternative approach for the treatment of human CC, for which Tivantinib may an effective inhibitor. The synergistic activation of the JNK/c-jun pathway contributed to the elevated apoptosis in CC cells via treatment with Tivantinib. |
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| Beschreibung: | Gesehen am 04.06.2019 |
| Beschreibung: | Online Resource |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-019-1460-1 |