PPARα agonist fenofibrate relieves acquired resistance to gefitinib in non-small cell lung cancer by promoting apoptosis via PPARα/AMPK/AKT/FoxOl pathway

• 作者: Mei-sa Wang Qiu-shuang Han Zhi-rong Jia Chuan-sheng Chen Chen Qiao Qian-qian Liu Ya-meng Zhang Kai-wei Wang Jie Wang Kang Xiao Xuan-sheng Ding
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2022,（1）
• 所属期刊栏目: Cbemotherapy
• 页码范围: 167-176
• 页数: 10页
• 语种: 英文

摘要

Recent studies show that intracellular accumulation of cholesterol leads to acquired resistance to gefitinib in non-small cell lung cancer(NSCLC)cells.In this study we investigated how to regulate the cholesterol levels in gefitinib-resistant NSCLC cells.We showed that intracellular cholesterol levels in gefitinib-resistant cell lines(PC-9/GR,H1975,H1650,and A549)were significantly higher than that in gefitinib-sensitive cell line(PC-9).Treatment with gefitinib(5 μM)significantly increased intracellular cholesterol levels in PC-9/GR,H1 975,and H1650 cells.Gefitinib treatment downregulated the expression of PPARα,LXRα,and ABCA1,leading to dysregulation of cholesterol efflux pathway.We found that a lipid-lowering drug fenofibrate(20,40 μM)dose-dependently increased the expression of PPARα,LXRα,and ABCA1,decreased the intracellular cholesterol levels,and enhanced the antiproliferative effects of gefitinib in PC-9/GR,H1 975,and H1650 cells.We revealed that fenofibrate increased the gefitinib-induced apoptosis via regulating the key proteins involved in the intrinsic apoptosis pathway.In PC-9/GR,H1975 and H1650 cells,fenofibrate dose-dependently increased the expression of AMPK,FoxO1,and decreased the expression of AKT,which were remarkably weakened by knockdown of PPARα.In PC-9/GR cell xenograft mice,combined administration of gefitinib(25 mg·kg-1·d-1)and fenofibrate(100 mg·kg-1·d-1)caused remarkable inhibition on tumor growth as compared to treatment with either drug alone.All the results suggest that fenofibrate relieves acquired resistance to gefitinib in NSCLC by promoting apoptosis via regulating PPARα/AMPK/AKT/FoxO1 pathway.We propose that combination of gefitinib and fenofibrate is a potential strategy for overcoming the gefitinib resistance in NSCLC.