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作者

Chunning Zheng, Hongxu Wang, Shuchao Zhao, Chaoqun Ma, Hengjun Gao, Faji Yang, Xu Zhou, Jun Lu, Chunqing Zhang, Huaqiang Zhu

作者单位

com. ¹⁰ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: zhengchunning@sdfmu.edu.cn. ² Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: zhouxu2008@sina.com. ⁸ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: medkaomcq@qq.com. ⁵ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China Department of General Surgery, Jiyang People's Hospital, Jinan, 251400, China. Electronic address: wanghongxu1104@16 Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: zhuhuaqiang@sdfmu.edu.cn. Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: fajiyang@foxmail.com. ⁷ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: lujun@sdfmu.edu.cn. ⁹ Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: 13583188661@16 Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China. Electronic address: cghj_561@16 com. ³ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China. Electronic address: 571685032@qq.com. ⁴ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China Affiliations ¹ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China com. ⁶ Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China

刊名

European journal of pharmacology

年份

2022

页码

175290

ISSN

1879-0712

关键词

Cholangiocarcinoma EG00229 Lenvatinib Neuropilin-1 c-Met

摘要

Neuropilin-1 participates in the progression of cholangiocarcinoma and lenvatinib is an approved tyrosine kinase inhibitor treating several other cancers. Our exploratory study reveals that the inhibitory activities of lenvatinib largely rely on the expression levels of NRP-1 in CCA cells, leading to the present study that aims to investigate whether inhibition of NRP-1 could enhance the effects of lenvatinib in suppressing CCA. By using stable transfected CCA cells depleted of NRP-1 and EG002...更多

Neuropilin-1 participates in the progression of cholangiocarcinoma and lenvatinib is an approved tyrosine kinase inhibitor treating several other cancers. Our exploratory study reveals that the inhibitory activities of lenvatinib largely rely on the expression levels of NRP-1 in CCA cells, leading to the present study that aims to investigate whether inhibition of NRP-1 could enhance the effects of lenvatinib in suppressing CCA. By using stable transfected CCA cells depleted of NRP-1 and EG00229, a specific NRP-1 inhibitor, we examined cell proliferation, cell cycle distribution and apoptosis, and detected the expression of key molecules and the involvement of the c-Met pathway. Xenograft mouse models were employed to verify the in vitro results. NRP-1 depletion and EG00229 strengthened lenvatinib in inhibiting the proliferation and promoting the apoptosis of CCA cells, and their additive or synergistic effects were confirmed in animal models. Mechanistically, lenvatinib induced the activation of the c-Met pathway, while either NRP-1 depletion or EG00229 inhibited this activation, which could be stimulated by its ligand hepatocyte growth factor. NRP-1 inhibition resulted in a significant alteration in the expression/activation of downstream pathways and molecules, which are key factors regulating cell proliferation and apoptosis. In conclusion, the present results indicate that the inhibition of NRP-1 enhances the efficacy of lenvatinib via the c-Met pathway, and warrant further studies on the pharmacological utility of EG00229, particularly, in the combination of lenvatinib as a promising adjunct therapeutic strategy for combating CCA.收起

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