title: Caffeic acid phenethyl ester (CAPE) revisited: Covalent modulation of XPO1/CRM1 activities and implication for its mechanism of action.
abstract: Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti-inflammatory, anticarcinogenic, antioxidant, and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE. In particular, we showed that CAPE could specifically target the non-catalytic and conserved Cys528of XPO1 through the means of mass spectrometric analysis. In addition, we demonstrated that the mutation of Cys528residue in XPO1 could rescue the nuclear export defects caused by CAPE. Furthermore, we performed position-restraint molecular dynamics simulation to show that the Michael acceptor moiety of CAPE is the warhead to enable covalent binding with Cys528residue of XPO1. The covalent modulation of nuclear export by CAPE may explain its diverse biological effects. Our findings may have general implications for further investigation of CAPE and its structural analogs.
authors.affiliation: Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: Sijin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: Keren
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Dalian Institute of Chemical Physics, National Chromatographic R&A Center, Chinese Academy of Sciences, Dalian, China.
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Qin
authors.affiliation: Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
authors.affiliation: School of Pharmacology, Dalian University of Technology, Dalian, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Dalian Institute of Chemical Physics, National Chromatographic R&A Center, Chinese Academy of Sciences, Dalian, China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Ye
authors.affiliation: Dalian Institute of Chemical Physics, National Chromatographic R&A Center, Chinese Academy of Sciences, Dalian, China.
authors.forename: Hanfa
authors.initials: H
authors.lastname: Zou
authors.affiliation: Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Yang
mesh_terms: D001665:Binding Sites; D002109:Caffeic Acids / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000032:analysis; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000097606:Exportin 1 Protein
chemical_list: D002109:Caffeic Acids; D028884:Karyopherins; D010455:Peptides; D010626:Phenylethyl Alcohol; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C055494:caffeic acid phenethyl ester
keywords: XPO1/CRM1; caffeic acid phenethyl ester; covalent binding; nuclear export