論文 - 詳細
| RRC ID | 54909 |
|---|---|
| 著者 | Wei K, Li M, Zöller M, Wang M, Mehrabi A, Hoffmann K. |
| タイトル | Targeting c-MET by Tivantinib through synergistic activation of JNK/c-jun pathway in cholangiocarcinoma. |
| ジャーナル | Cell Death Dis |
| Abstract |
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. |
| 巻・号 | 10(3) |
| ページ | 231 |
| 公開日 | 2019-3-8 |
| DOI | 10.1038/s41419-019-1460-1 |
| PII | 10.1038/s41419-019-1460-1 |
| PMID | 30850583 |
| PMC | PMC6408560 |
| MeSH | Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Apoptosis / drug effects Bile Duct Neoplasms / drug therapy* Bile Duct Neoplasms / enzymology Bile Duct Neoplasms / pathology Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Cholangiocarcinoma / drug therapy* Cholangiocarcinoma / enzymology Cholangiocarcinoma / pathology Hepatocyte Growth Factor / pharmacology Humans JNK Mitogen-Activated Protein Kinases / metabolism MAP Kinase Kinase 4 / genetics MAP Kinase Kinase 4 / metabolism MAP Kinase Signaling System / drug effects* Middle Aged Phosphorylation / drug effects Proto-Oncogene Proteins c-met / antagonists & inhibitors Proto-Oncogene Proteins c-met / genetics Proto-Oncogene Proteins c-met / metabolism* Pyrrolidinones / pharmacology* Pyrrolidinones / therapeutic use Quinolines / pharmacology* Quinolines / therapeutic use RNA, Small Interfering / metabolism |
| IF | 5.959 |
| 引用数 | 2 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HuCCT1(RCB1960) TFK-1(RCB2537) |