Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer  

作　　者：Ling-bing Li Ling-xiao Yang Lei Liu Fan-rong Liu Alex H.Li Yi-lin Zhu Hao Wen Xia Xue Zhong-xian Tian Hong Sun Pei-chao Li Xiao-gang Zhao 

机构地区：[1]Department of Thoracic Surgery,The Second Hospital,Cheeloo College of Medicine,Shandong University,Ji-nan,250012,China [2]Division of Environmental Medicine,Department of Medicine,New York University Grossman School of Medicine,New York,NY,10010,USA [3]Department of Pharmacy,The Second Hospital,Cheeloo College of Medicine,Shandong University,Ji-nan,250012,China [4]Key Laboratory of Chest Cancer,The Second Hospital,Cheeloo College of Medicine,Shandong University,Ji-nan,250012,China

出　　处：《Acta Pharmacologica Sinica》2024年第5期1060-1076,共17页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.81874396);Ji-nan Clinical Medicine Research Program for Thoracic Cancer(No.201912007);a grant from the Special Construction Project Fund for Taishan Scholars of Shandong Province.

摘　　要：Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer(NSCLC)patients,and currently,there is no promising drug for paclitaxel resistance.In this study,we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines.We constructed paclitaxel-resistant NSCLC cell lines(A549/PR and H460/PR)by long-term exposure to paclitaxel.We found that triptolide,a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F,effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro.Through high-throughput sequencing,we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process.We demonstrated that triptolide directly bound to HNF1A,one of the transcription factors of SHH,and inhibited HNF1A/SHH expression,ensuing in attenuation of Hedgehog signaling.In NSCLC tumor tissue microarrays and cancer network databases,we found a positive correlation between HNF1A and SHH expression.Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A,thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1.This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance.

关 键 词：non-small cell lung cancer paclitaxel resistance TRIPTOLIDE ABCB1 HNF1A Sonic Hedgehog 

分 类 号：R96[医药卫生—药理学]