title: Anti-angiogenic activity of PSA-derived peptides.
abstract: BACKGROUND
  PSA is a biomarker for diagnosis and management of prostate cancer. PSA is known to have anti-tumorigenic activities, however, the physiological role of PSA in prostate tumor progression is not well understood.
  
  
  METHODS
  Five candidate peptides identified based upon computer modeling of the PSA crystal structure and hydrophobicity were synthesized at >95% purity. The peptides in a linear form, and a constrained form forced by a di-sulfide bond joining the two ends of the peptide, were investigated for anti-angiogenic activity in HUVEC.
  
  
  RESULTS
  None of the five PSA-mimetic peptides exhibited PSA-like serine protease activity. Two of the peptides demonstrated significant anti-angiogenic activity in HUVEC based on (i) inhibition of cell migration and invasion; (ii) inhibition of tube formation in Matrigel; (iii) anti-angiogenic activity in a sprouting assay; and (iv) altered expression of pro- and anti-angiogenic growth factors. Constrained PSA-mimetic peptides had greater anti-angiogenic activity than the corresponding linearized form. Complexing of PSA with ACT eliminated PSA enzymatic activity and reduced anti-angiogenic activity. In contrast, ACT had no effect on the anti-angiogenic effects of the linear or constrained PSA-mimetic peptides. Modeling of the ACT-PSA complex demonstrated ACT sterically blocks the anti-angiogenic activity of the two bioactive peptides.
  
  
  CONCLUSIONS
  The interaction of a hydrophilic domain on the surface of the PSA molecule with a target on the cell membrane of prostate endothelial and epithelial cells was responsible for the anti-angiogenic or anti-tumorigenic activity of PSA: enzymatic activity was not associated with anti-angiogenic effects. Furthermore, since PSA and ACT are both expressed within the human prostate tissue microenvironment, the balance of their expression may represent a mechanism for endogenous regulation of tissue angiogenesis.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kailash C
authors.initials: KC
authors.lastname: Chadha
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.|Division of Allergy/Immunology & Rheumatology, Department of Medicine, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Bindukumar
authors.initials: B
authors.lastname: Nair
authors.affiliation: Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Godoy
authors.affiliation: Department of Pharmacology & Toxicology, State University of New York at Buffalo, Buffalo, NewYork.
authors.forename: Rajendram
authors.initials: R
authors.lastname: Rajnarayanan
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Erik
authors.initials: E
authors.lastname: Nabi
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Rita
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Neel R
authors.initials: NR
authors.lastname: Patel
authors.affiliation: Division of Allergy/Immunology & Rheumatology, Department of Medicine, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Aalinkeel
authors.affiliation: Division of Allergy/Immunology & Rheumatology, Department of Medicine, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Schwartz
authors.affiliation: Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Smith
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000737:chemistry / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D020533:Angiogenesis Inhibitors; D010455:Peptides; D017430:Prostate-Specific Antigen
keywords: HUVEC; PSA-ACT complex; QPCR; in-vitro angiogenesis; prostate cancer; theoretical model