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: Rajeshwari R Mehta, Tohru Yamada, Brad N Taylor, Konstantin Christov, Marissa L King, Dibyen Majumdar, Fatima Lekmine, Chinnaswamy Tiruppathi, Anne Shilkaitis, Laura Bratescu, Albert Green, Craig W Beattie, Tapas K Das Gupta
• Journal: Angiogenesis (Angiogenesis) Vol. 14 Issue 3 Pg. 355-69 (Sep 2011) ISSN: 1573-7209 [Electronic] Germany
• PMID: 21667138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Antineoplastic Agents
• Cell-Penetrating Peptides
• Peptide Fragments
• Platelet Endothelial Cell Adhesion Molecule-1
• Azurin
• Vascular Endothelial Growth Factor Receptor-2
• Focal Adhesion Kinase 1
• PTK2 protein, human
• Proto-Oncogene Proteins c-akt
• azurin (50-77)

Topics

• Actins (metabolism)
• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics)
• Azurin (chemistry, pharmacology)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement
• Cell-Penetrating Peptides (chemistry, pharmacology)
• Clinical Trials, Phase II as Topic
• Endothelial Cells (metabolism, pathology)
• Focal Adhesion Kinase 1 (metabolism)
• Focal Adhesions (metabolism)
• Humans
• Mice
• Mice, Nude
• Neoplasms (drug therapy, metabolism, pathology)
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Peptide Fragments (chemistry, pharmacology)
• Phosphorylation (drug effects)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pseudomonas aeruginosa (chemistry)
• Umbilical Veins (metabolism, pathology)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)