title: A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2, FAK and Akt.
abstract: Amino acids 50-77 (p28) of azurin, a 128 aa cupredoxin isolated from Pseudomonas aeruginosa, is essentially responsible for azurin's preferential penetration of cancer cells. We now report that p28 also preferentially penetrates human umbilical vein endothelial cells (HUVEC), co-localized with caveolin-1 and VEGFR-2, and inhibits VEGF- and bFGF-induced migration, capillary tube formation and neoangiogenesis in multiple xenograft models. The antiangiogenic effect of p28 in HUVEC is associated with a dose-related non-competitive inhibition of VEGFR-2 kinase activity. However, unlike other antiangiogenic agents that inhibit the VEGFR-2 kinase, p28 decreased the downstream phosphorylation of FAK and Akt that normally precedes cellular repositioning of the cytoskeletal (F-actin), focal adhesion (FAK and paxillin), and cell to cell junction protein PECAM-1, inhibiting HUVEC motility and migration. The decrease in pFAK and pAkt levels suggests that p28 induces a pFAK-mediated loss of HUVEC motility and migration and a parallel Akt-associated reduction in cell matrix attachment and survival. This novel, direct antiangiogenic effect of p28 on endothelial cells may enhance the cell cycle inhibitory and apoptotic properties of this prototype peptide on tumor cell proliferation as it enters a Phase II clinical trial.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, UIC College of Medicine, Chicago, IL 60612, USA.
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Mehta
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamada
authors.forename: Brad N
authors.initials: BN
authors.lastname: Taylor
authors.forename: Konstantin
authors.initials: K
authors.lastname: Christov
authors.forename: Marissa L
authors.initials: ML
authors.lastname: King
authors.forename: Dibyen
authors.initials: D
authors.lastname: Majumdar
authors.forename: Fatima
authors.initials: F
authors.lastname: Lekmine
authors.forename: Chinnaswamy
authors.initials: C
authors.lastname: Tiruppathi
authors.forename: Anne
authors.initials: A
authors.lastname: Shilkaitis
authors.forename: Laura
authors.initials: L
authors.lastname: Bratescu
authors.forename: Albert
authors.initials: A
authors.lastname: Green
authors.forename: Craig W
authors.initials: CW
authors.lastname: Beattie
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Das Gupta
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001400:Azurin / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology*; D017322:Clinical Trials, Phase II as Topic; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D014471:Umbilical Veins / Q000378:metabolism / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D010446:Peptide Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D001400:Azurin; D040301:Vascular Endothelial Growth Factor Receptor-2; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C561466:azurin (50-77)