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Targeting c-MET by Tivantinib through synergistic activation of JNK/c-jun pathway in cholangiocarcinoma.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-03-08 , DOI: 10.1038/s41419-019-1460-1 Kai Wei 1 , Mao Li 1 , Margot Zöller 1 , Meng Wang 1 , Arianeb Mehrabi 1 , Katrin Hoffmann 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-03-08 , DOI: 10.1038/s41419-019-1460-1 Kai Wei 1 , Mao Li 1 , Margot Zöller 1 , Meng Wang 1 , Arianeb Mehrabi 1 , Katrin Hoffmann 1
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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.
中文翻译：
Tivantinib通过协同激活胆管癌中JNK / c-jun途径靶向c-MET。
人类胆管癌（CC）的临床治疗选择有限。c-MET是肝细胞生长因子（HGF）的高亲和力受体，在许多癌症中均被放松调节。其在胆管癌发生中的作用尚不清楚。在当前的研究中，分析了23例相应的肿瘤组织和非肿瘤组织，这些组织取自接受肝切除的肝内（iCC）和肝门周围胆管癌（pCC）患者。评价了临床病理特征与c-MET以及c-jun N末端激酶（JNK）的关系。在三种人CC细胞系HUCC-T1，TFK-1和EGI-1中研究了具有抗c-MET激酶活性的小分子抑制剂Tivantinib的抗肿瘤作用。与在非肿瘤组织样品中获得的结果相比，c-MET在91.3％的肿瘤组织中过表达（p < 0.01）。在17.4％的患者中，肿瘤组织中的JNK表达高于相应的非肿瘤组织样品（p <0.01）。抑制人CC细胞系中c-MET异常表达的方法是用Tivantinib阻断c-MET的磷酸化。检测到细胞活力和集落形成能力显着下降（p <0.01）。Tivantinib治疗后证明了JNK / c-jun途径的协同激活。观察到通过siRNA抑制JNK或通过刺激HGF拮抗Tivantinib产生的c-MET受体竞争性结合。我们的数据表明，抑制c-MET可能是治疗人CC的一种可能的替代方法，替万替尼可能是一种有效的抑制剂。
更新日期：2019-03-09
中文翻译：
Tivantinib通过协同激活胆管癌中JNK / c-jun途径靶向c-MET。
人类胆管癌（CC）的临床治疗选择有限。c-MET是肝细胞生长因子（HGF）的高亲和力受体，在许多癌症中均被放松调节。其在胆管癌发生中的作用尚不清楚。在当前的研究中，分析了23例相应的肿瘤组织和非肿瘤组织，这些组织取自接受肝切除的肝内（iCC）和肝门周围胆管癌（pCC）患者。评价了临床病理特征与c-MET以及c-jun N末端激酶（JNK）的关系。在三种人CC细胞系HUCC-T1，TFK-1和EGI-1中研究了具有抗c-MET激酶活性的小分子抑制剂Tivantinib的抗肿瘤作用。与在非肿瘤组织样品中获得的结果相比，c-MET在91.3％的肿瘤组织中过表达（p < 0.01）。在17.4％的患者中，肿瘤组织中的JNK表达高于相应的非肿瘤组织样品（p <0.01）。抑制人CC细胞系中c-MET异常表达的方法是用Tivantinib阻断c-MET的磷酸化。检测到细胞活力和集落形成能力显着下降（p <0.01）。Tivantinib治疗后证明了JNK / c-jun途径的协同激活。观察到通过siRNA抑制JNK或通过刺激HGF拮抗Tivantinib产生的c-MET受体竞争性结合。我们的数据表明，抑制c-MET可能是治疗人CC的一种可能的替代方法，替万替尼可能是一种有效的抑制剂。
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