Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis - 22/03/24

Doi : 10.1016/j.biopha.2024.116304

Qiuyan Guo ^a,^{^{1
Authors contributed equally to this work},}^{^{2
0009-0007-8005-3995}}, Minghong Zhao ^c,^{^{1
Authors contributed equally to this work}}, Qixin Wang ^a,^{^{1
Authors contributed equally to this work}}, Tianming Lu ^a, Piao Luo ^a, Lin Chen ^a, Fei Xia ^a, Huanhuan Pang ^a, Shengnan Shen ^a, Guangqing Cheng ^a, Chuanhao Dai ^a, Yuqing Meng ^a, Tianyu Zhong ^c,^⁎,^{^{1
Authors contributed equally to this work}} , Chong Qiu ^a,^⁎,^{^{1
Authors contributed equally to this work},}^{^{3
0000-0001-6343-5480}} , Jigang Wang ^a,^b,^⁎,^{^{1
Authors contributed equally to this work}}
^a State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
^b Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital; First Affiliated Hospital of Southern University of Science and Technology; Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
^c First Affiliated Hospital of Gannan Medical University, No. 23, Qingnian Road, Ganzhou, Jiangxi 341000, China

^⁎Corresponding authors.^⁎⁎Corresponding author at: State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaState Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesBeijing100700China

Abstract

Glycyrrhetinic acid (GA) shows great efficiency against non-small cell lung cancer (NSCLC), but the detailed mechanism is unclear, which has limited its clinical application. Herein, we investigated the potential targets of GA against NSCLC by activity-based protein profiling (ABPP) technology and the combination of histopathology and proteomics validation. In vitro and in vivo results indicated GA significantly inhibited NSCLC via promotion of peroxiredoxin-6 (Prdx6) and caspase-3 (Casp3)-mediated mitochondrial apoptosis. This original finding will provide theoretical and data support to improve the treatment of NSCLC with the application of GA.

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Graphical Abstract

Structural illustration of glycyrrhetinic acid inhibiting non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis detected by activity-based protein profiling technology and the combination of histopathology and proteomics validation.

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Highlights

•	First-time integrated analysis profiling of non-small cell lung cancer (NSCLC) and Glycyrrhetinic acid (GA) treatment by integrating activity-based protein profiling (ABPP) technology, histopathology and proteomics validation both in vitro and in vivo.
•	Identification of GA promoted ROS accumulation and inhibited proliferation of NSCLC cells.
•	Identification of Casp3 and Prdx6 were direct target proteins of GA in the treatment of NSCLC cells.

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Abbreviations : ABPP, ATP, BCA, Casp3, CCK8, CETSA-WB, DCFH-DA, DEGs, DEPs, DMEM, DMSO, DTT, FBS, GA, GAPDH, GO, HE, IAA, IAA-yne, KEGG, LC-MS, LLC, NSCLC, PBS, Prdx6, ROS, TBTA, TCEP, TEAB

Keywords : Glycyrrhetinic acid, NSCLC, Activity-based protein profiling

Plan

Introduction

Results

GA promoted ROS accumulation and inhibited proliferation of NSCLC cells

GA promoted mitochondrial membrane damage

Identification of GA-interacting proteins by fluorescence labeling and mass spectrometry

Casp3 and Prdx6 are direct target proteins of GA in LLC cells

Casp3 inhibitor attenuated GA-induced apoptosis and ROS accumulation in LLC cells

GA reduced the growth rate of LLC cell tumors in mice

Identification of key target proteins of GA in NSCLC mice via proteomics

Examination of the correlation of GA targets with ROS and the tumor immune microenvironment

Discussion

Materials and methods

Reagents

Cell culture

Detection of apoptosis-related indicators

Measurement of ROS

Cellular fluorescence imaging

Competitive fluorescent labeling of GA with IAA-yne in LLC cells

Mass spectroscopic analysis of labeled proteins in LLC cells

Protein purification

LLC-induced NSCLC mouse model and drug treatment

Detection of NSCLC cell growth

Proteomic analysis of lung tissue

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Article 116304- avril 2024 Retour au numéro

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Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis - 22/03/24

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