title: Inhibition of formyl peptide receptor in high-grade astrocytoma by CHemotaxis Inhibitory Protein of S. aureus.
abstract: BACKGROUND
  High-grade astrocytomas are malignant brain tumours that infiltrate the surrounding brain tissue and have a poor prognosis. Activation of formyl peptide receptor (FPR1) on the human astrocytoma cell line U87 promotes cell motility, growth and angiogenesis. We therefore investigated the FPR1 inhibitor, Chemotaxis Inhibitory Protein of S. aureus (CHIPS), as a potential anti-astrocytoma drug.
  
  
  RESULTS
  FPR1 expression was studied immunohistochemically in astrocytomas WHO grades I-IV. With intracellular calcium mobilisation and migration assays, human ligands were tested for their ability to activate FPR1 on U87 cells and on a cell line derived from primary astrocytoma grade IV patient material. Thereafter, we selectively inhibited these ligand-induced responses of FPR1 with an anti-inflammatory compound called Chemotaxis Inhibitory Protein of S. aureus (CHIPS). U87 xenografts in NOD-SCID mice served to investigate the effects of CHIPS in vivo. FPR1 was expressed in 29 out of 32 (90%) of all grades of astrocytomas. Two human mitochondrial-derived formylated peptides, formyl-methionil-leucine-lysine-isoleucine-valine (fMLKLIV) and formyl-methionil-methionil-tyrosine-alanine-leucine-phenylalanine (fMMYALF), were potent activators of FPR1 on tumour cells. Ligand-induced responses of FPR1-expressing tumour cells could be inhibited with FPR1 inhibitor CHIPS. Treatment of tumour-bearing mice with CHIPS slightly reduced tumour growth and improved survival as compared to non-treated animals (P=0.0019).
  
  
  CONCLUSIONS
  Targeting FPR1 with CHIPS reduces cell motility and tumour cell activation, and prolongs the survival of tumour-bearing mice. This strategy could be explored in future research to improve treatment results for astrocytoma patients.
authors: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
authors: J C
authors: JC
authors: Boer
authors: U M
authors: UM
authors: Domanska
authors: H
authors: H
authors: Timmer-Bosscha
authors: I G J
authors: IG
authors: Boer
authors: C J C
authors: CJ
authors: de Haas
authors: J V
authors: JV
authors: Joseph
authors: F A E
authors: FA
authors: Kruyt
authors: E G E
authors: EG
authors: de Vries
authors: W F A
authors: WF
authors: den Dunnen
authors: J A G
authors: JA
authors: van Strijp
authors: A M E
authors: AM
authors: Walenkamp
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D001426:Bacterial Proteins / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060787:Neoplasm Grading; D010446:Peptide Fragments / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D001426:Bacterial Proteins; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; C493134:chemotaxis inhibitory protein, Staphylococcus aureus; D002118:Calcium