Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation  

作　　者：Paula Fernández-Palanca Tania Payo-Serafín Beatriz San-Miguel Carolina Méndez-Blanco María J.Tuñón Javier González-Gallego JoséL.Mauriz 

机构地区：[1]Institute of Biomedicine(IBIOMED),University of León,Campus de Vegazana s/n,24071 León,Spain [2]Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas(CIBERehd),Instituto de Salud Carlos Ⅲ,Av.de Monforte de Lemos,5,28029 Madrid,Spain

出　　处：《Acta Pharmacologica Sinica》2023年第5期1066-1082,共17页中国药理学报（英文版）

基　　金：supported by the Ministry of Science and Innovation of Spain(MCIN/AEI/10.13039/501100011033)[project PID2020-119164RB-I00];CIBERehd is funded by Instituto de Salud CarlosⅢ(ISCⅢ),Spain.PFP is supported by the Ministry of Education of Spain(MCIN/AEI/10.13039/501100011033)[grant FPU17/01995]and TPS by the Asociacion Espanola Contra el Cancer(AECC)-Junta Provincial de Leon,Spain.

摘　　要：Despite pharmacological advances such as lenvatinib approval,therapeutic failure of hepatocellular carcinoma(HCC)remains a big challenge due to the complexity of its underlying molecular mechanisms.Neuropilin-1(NRP1)is a co-receptor involved in several cellular processes associated to chemoresistance development.Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness,herein we investigated the interplay among NRP1,autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines.We first analyzed NRP1 expression levels in human HCC samples from public databases,found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages.Among 3 HCC cell lines(HepG2,Huh-7 and Hep3B),Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib.We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells.Furthermore,lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells;co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib,and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1.In addition,exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells.Under hypoxia,HIF-1αdirectly modulated NRP1 expression;HIF-1αsilencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia,but also prevented the loss of effectiveness caused by bafilomycin A1,highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation.Overall,NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure der

关 键 词：hepatocellular carcinoma cells NEUROPILIN-1 AUTOPHAGY HYPOXIA HIF-1Α lenvatinib 

分 类 号：R734.2[医药卫生—肿瘤]