Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosisOA北大核心
Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis
Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demon-strated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel anti-angiogenic therapy for endometriosis.
Sze Wan Hung;Yi Song;Yao Wang;Jacqueline Pui Wah Chung;Tak Hang Chan;Roman A.Zubarev;Chi Chiu Wang;Massimiliano Gaetani;Yiran Li;Zhouyurong Tan;Xu Zheng;Ruizhe Zhang;Yang Ding;Gene Chi Wai Man;Tao Zhang
Department of Obstetrics & Gynaecology,The Chinese University of Hong Kong,Hong Kong,ChinaDepartment of Chemistry,McGill University,Montreal,H3A2K6,CanadaDivision of Physiological Chemistry I,Department of Medical Biochemistry and Biophysics,Karolinska Institutet,Stockholm,SE 17177,Sweden||Unit of Chemical Proteomics,Science for Life Laboratory(SciLifeLab),Stockholm,SE 17177,Sweden||Department of Pharmacological & Technological Chemistry,I.M.Sechenov First Moscow State Medical University,Moscow,119146,RussiaDepartment of Obstetrics & Gynaecology,The Chinese University of Hong Kong,Hong Kong,China||Reproduction and Development,Li Ka Shing Institute of Health Sciences,The Chinese University of Hong Kong,Hong Kong,China||School of Biomedical Sciences,The Chinese University of Hong Kong,Hong Kong,China||Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine,The Chinese University of Hong Kong,Hong Kong,ChinaDivision of Physiological Chemistry I,Department of Medical Biochemistry and Biophysics,Karolinska Institutet,Stockholm,SE 17177,Sweden||Chemical Proteomics Core Facility,Department of Medical Biochemistry and Biophysics,Karolinska Institutet,Stockholm,SE 17177,Sweden||Unit of Chemical Proteomics,Science for Life Laboratory(SciLifeLab),Stockholm,SE 17177,SwedenDepartment of Obstetrics & Gynaecology,The Chinese University of Hong Kong,Hong Kong,China||Center for Reproductive Medicine,Henan Key Laboratory of Reproduction and Genetics,The First Affiliated Hospital of Zhengzhou University,Zhengzhou,450003,China
Molecular targetsProEGCGEGCGAngiogenesisTreatmentEndometriosis
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This work was supported by the GRF RGC & CRF,Hong Kong(Grant Nos.:475012 and C5045-20 EF);HMRF,Hong Kong(Grant No.:03141386);ITF,Hong Kong(Grant No.:ITS/209/12);UGC Direct Grant 2011,2012,2021.032;HKOG Trust Fund 2011,2014,2019;and the National Natural Science Foundation of China(Grant Nos.:81974225 and 82201823).The Chemical proteomics core facility at Biomedicum(MBB,Karolinska Institute),also the Unit of SciLifeLab and part of the Swedish National Infrastructure for Biological Mass Spectrometry(BioMS),provided full support in the experimental design and the performance of the proteomics analysis using the Proteome Integral Solubility Alteration(PISA)assay for target dis-covery,with relative data analysis.
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