title: Epigallocatechin-gallate suppresses tumorigenesis by directly targeting Pin1.
abstract: The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). The human peptidyl prolyl cis/trans isomerase (Pin1) plays a critical role in oncogenic signaling. Herein, we report the X-ray crystal structure of the Pin1/EGCG complex resolved at 1.9 Å resolution. Notably, the structure revealed the presence of EGCG in both the WW and PPIase domains of Pin1. The direct binding of EGCG with Pin1 was confirmed and the interaction inhibited Pin1 PPIase activity. In addition, proliferation of cells expressing Pin1 was inhibited and tumor growth in a xenograft mouse model was suppressed. The binding of EGCG with Arg17 in the WW domain prevented the binding of c-Jun, a well-known Pin1 substrate. EGCG treatment corresponded with a decreased abundance of cyclin D1 and diminution of 12-O-tetradecanoylphorbol-l3-acetate-induced AP-1 or NF-κB promoter activity in cells expressing Pin1. Overall, these results showed that EGCG directly suppresses the tumor-promoting effect of Pin1.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA. zgdong@hi.umn.edu
authors.forename: Darya V
authors.initials: DV
authors.lastname: Urusova
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Zykova
authors.forename: Andria
authors.initials: A
authors.lastname: Carper
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009368:Neoplasm Transplantation; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D002392:Catechin; C045651:epigallocatechin gallate; D005982:Glutathione Transferase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D013755:Tetradecanoylphorbol Acetate