The activation of SIRT1 by resveratrol reduces breast cancer metastasis to lung through inhibiting neutrophil extracellular traps

AbstractNeutrophil extracellular traps (NETs) play a crucial role in breast cancer metastasis. However, the therapeutic target of NETs in breast cancer metastasis is still unknown. Using a natural metabolite library and single-cell sequencing data analysis, we identified resveratrol (RES), a polyphenolic natural phytoalexin, and agonist of silent information regulator-1 (SIRT1) that suppressed NETs formation after cathepsin C (CTSC) treatment. In vivo, RES significantly hindered breast cancer metastasis in a murine orthotopic 4T1 breast cancer model. Serum levels of myeloperoxidase-DNA and neutrophil elastase-DNA in mouse breast cancer model were significantly lower after RES treatment. Correspondingly, the tumour infiltrated CD8+T cells in the lungs increased after the treatment. Mechanistically, RES targets SIRT1 in neutrophils and significantly inhibits the citrullination of histones H3, which is essential for chromatin decondensation and NETs formation. Furthermore, we identified that the NETs were suppressed by RES in bone marrow neutrophils after CTSC treatment, while specific deficiency of SIRT1 in neutrophils promoted NETs formation and breast cancer to lung metastasis. Thus, our results revealed that RES could be potentially identified as a viable therapeutic drug to prevent neutrophil cell death and breast cancer metastasis.Keywords: Breast cancercancer metastasisresveratrolneutrophilneutrophil extracellular traps AcknowledgmentsThe authors thank the flow cytometry and imaging core facilities in Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine. We thank the flow cytometry core facility and imaging core facility in Shanghai Institute of Immunology for technical support with flow cytometry and confocal analysis. We thank Naijun Miao for providing supports for immunofluorescence staining of NETs. We also thank Ling-zhijie Kong and Qingliang Fang for tumor mouse model establishing.Author contributionsWenyan Yu and Zhuning Wang designed and performed experiments. Ping Dai, Jing Sun and Wenyan Yu analysed data and interpreted results. Jian Li and Wei Han helped with the experiments. Kaichun Li supervised the study and wrote the manuscript.Disclosure statementThe authors declare no potential conflicts of interest.Ethics approval and consent to participateThis study was approved by Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai, China. Animal experiments were approved by the Animal ethics committee of Shanghai Tongji Biomedical Technology Co., Ltd (No. TJBH01021101), in compliance with Guidelines for the Ethical Review of Laboratory Animal Welfare (GB/T 35892-2018) for the care and use of animals.Data availability statementThe raw data supporting the conclusion of this article will be made available by the authors without undue reservation.Additional informationFundingThis work was funded by the research project of Shanghai Fourth People's Hospital (sykyqd 701, 702 and xkzt-2022-1019), and by the scientific research project of Hongkou District Health Committee of Shanghai (No.2302-09).