Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway

Guiqin Ye; Xin Sun; Jiuzhou Li; Yuanyuan Mai; Ruilan Gao; Jianbin Zhang

doi:10.1016/j.jpha.2023.12.016

Volume 14 Issue 6

Jun. 2024

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Guiqin Ye, Xin Sun, Jiuzhou Li, Yuanyuan Mai, Ruilan Gao, Jianbin Zhang. Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway[J]. Journal of Pharmaceutical Analysis, 2024, 14(6): 100926. doi: 10.1016/j.jpha.2023.12.016

Citation:

Guiqin Ye, Xin Sun, Jiuzhou Li, Yuanyuan Mai, Ruilan Gao, Jianbin Zhang. Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway[J]. Journal of Pharmaceutical Analysis, 2024, 14(6): 100926. doi: 10.1016/j.jpha.2023.12.016

Citation:

Guiqin Ye, Xin Sun, Jiuzhou Li, Yuanyuan Mai, Ruilan Gao, Jianbin Zhang. Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway[J]. Journal of Pharmaceutical Analysis, 2024, 14(6): 100926. doi: 10.1016/j.jpha.2023.12.016

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Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway

doi: 10.1016/j.jpha.2023.12.016

Guiqin Ye^a,b,c,
Xin Sun^a,
Jiuzhou Li^d,
Yuanyuan Mai^c,
Ruilan Gao^{e
,
,},
Jianbin Zhang^{a
,
,}

a. 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;
b. Clinical Laboratory, Yuhuan City Hospital, Taizhou, Zhejiang, 317600, China;
c. Hangzhou Medical College, Hangzhou, 311300, China;
d. Department of Neurosurgery, Binzhou People's Hospital, Binzhou, Shandong, 256600, China;
e. Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310060, China

Funds:

This study was supported by the National Natural Science Foundation of China (Grant No.: 32070740), Zhejiang Provincial Natural Science Foundation (Grant No.: LZ23H160005), Natural Science Foundation of Jiangsu Province (Grant No.: BK20201197), and Zhejiang Provincial Outstanding Talent Project of Ten Thousand Talents Program, Zhejiang Provincial Qianjiang Talents Program to Jianbin Zhang.

Received Date: Oct. 20, 2023
Accepted Date: Dec. 19, 2023
Rev Recd Date: Dec. 15, 2023
Publish Date: Dec. 22, 2023

Abstract

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.
- Moracin N,
- Click chemistry,
- PD-L1,
- T cell,
- Lung cancer

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References(49)

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