title: Identification of oligomer proanthocyanidins (F2) isolated from grape seeds as a formyl peptide receptor 1 partial agonist.
abstract: Formyl peptide receptor 1 (FPR1) plays an important role in the rapid progression of glioblastoma and has been considered as a molecular target for the treatment. Previously, we have shown that oligomer proanthocyanidins (F2, degree of polymerization 2-15), isolated from grape seeds, inhibited FPR1-mediated chemotaxis of U-87 glioblastoma cells. In the present study, we investigated the capacity of F2 to interact with FPR1. The cross attenuation of chemotaxis revealed that F2 shared FPR1 with formyl-methionyl-leucyl-phenylalanine (fMLF), which is a prototype agonist of FPR1. F2 was chemotactic for U-87 cells, and the chemotactic response was abolished when FPR1 gene was silenced or FPR1 was competitively occupied. We further show that F2 specifically blocked the binding of fluorescent agonist to FPR1. Interestingly, F2 exhibited the characteristic of a partial agonist for FPR1, as shown by its capacity to activate FPR1-mediated PI3K-PKC-MAPK pathways. Meanwhile, F2 also attenuated fMLF-triggered MAPK activation, suggesting that F2 could antagonize the effect of an agonist. Furthermore, F2 abolished the invasion of U-87 cells induced by fMLF. Thus, we have identified F2 as a novel, partial agonist for FPR1, which may be useful for glioblastoma therapy.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016, Shenyang, Engineering Technology and Research Center for Plant Polyphenols of Liaoning Province, 110016 Shenyang, PR China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhao
authors.forename: Baoshan
authors.initials: B
authors.lastname: Sun
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Hou
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Li
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D001667:Binding, Competitive; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D056604:Grape Seed Extract / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D044945:Proanthocyanidins / Q000302:isolation & purification / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000235:genetics; D012639:Seeds / Q000737:chemistry; D014162:Transfection; D027843:Vitis / Q000737:chemistry*
chemical_list: C469986:FPR1 protein, human; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D044945:Proanthocyanidins; D044042:Receptors, Formyl Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium