Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway
10.1016/j.jpha.2023.12.016
- Author:
Ye GUIQIN
1
;
Sun XIN
;
Li JIUZHOU
;
Mai YUANYUAN
;
Gao RUILAN
;
Zhang JIANBIN
Author Information
1. Cancer Center,Department of Medical Oncology,Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province,Zhejiang Provincial People's Hospital,Affiliated People's Hospital,Hangzhou Medical College,Hangzhou,310014,China;Clinical Laboratory,Yuhuan City Hospital,Taizhou,Zhejiang,317600,China;Hangzhou Medical College,Hangzhou,311300,China
- Keywords:
Moracin N;
Click chemistry;
PD-L1;
T cell;
Lung cancer
- From:
Journal of Pharmaceutical Analysis
2024;14(6):914-925
- CountryChina
- Language:Chinese
-
Abstract:
Lung cancer ranks the top of malignancies that cause cancer-related deaths worldwide.The leaves of Morus alba L are traditional Chinese medicine widely applied in respiratory diseases.Our previous work has demonstrated the anti-lung cancer effect of secondary metabolites of mulberry leaf,but their mechanism of action has still not fully elucidated.We synthesized Moracin N(MAN)-Probe conjugated with alkyne to label lung cancer cells and identified protein targets by chemical proteomic analysis.MAN and its probe exerted similar growth-inhibitory effect on human lung cancer cells.Chemical proteomic results showed that MAN targeted the programmed death ligand 1(PD-L1)checkpoint pathway and T cell receptor(TCR)signaling pathway,indicating its immune-regulatory function.Cell-free surface plasmon resonance(SPR)results showed the direct interaction of MAN with PD-L1 protein.Molecular docking analysis demonstrated that MAN bound to E158 residue of PD-L1 protein.MAN downregulated the expression levels of PD-L1 in a time-and dose-dependent manner and disrupted the PD-L1/programmed death 1(PD-1)binding,including other secondary metabolites of mulberry leaves Guangsangon E(GSE)and Chalcomoracin(CMR).Human peripheral blood mononuclear cells(PBMCs)co-cultured with MAN-treated A549 cells,resulting in the increase of CD8+GZMB+T cells and the decrease of CD8+PD-1+T cells.It suggested that MAN exerts anti-cancer effect through blocking the PD-L1/PD-1 signaling.In vivo,MAN combined with anti-PD-1 antibody significantly inhibited lung cancer development and metastasis,indicating their synergistic effect.Taken together,secondary metabolites of mulberry leaves target the PD-L1/PD-1 signaling,enhance T cell-mediated immunity and inhibit the tumorigenesis of lung cancer.Their modulatory effect on tumor microenvironment makes them able to enhance the therapeutic efficacy of immune checkpoint inhibitors in lung cancer.
