Angiogenesis

, Volume 14, Issue 3, pp 355–369

A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2, FAK and Akt

  • 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
Original Paper

DOI: 10.1007/s10456-011-9220-6

Cite this article as:
Mehta, R.R., Yamada, T., Taylor, B.N. et al. Angiogenesis (2011) 14: 355. doi:10.1007/s10456-011-9220-6

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.

Keywords

Azurin Angiogenesis FAK Akt p53 HUVEC 

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Rajeshwari R. Mehta
    • 1
  • Tohru Yamada
    • 1
  • Brad N. Taylor
    • 1
  • Konstantin Christov
    • 1
  • Marissa L. King
    • 2
  • Dibyen Majumdar
    • 2
  • Fatima Lekmine
    • 1
  • Chinnaswamy Tiruppathi
    • 3
  • Anne Shilkaitis
    • 1
  • Laura Bratescu
    • 1
  • Albert Green
    • 1
  • Craig W. Beattie
    • 1
  • Tapas K. Das Gupta
    • 1
  1. 1.Department of Surgery, Division of Surgical OncologyUIC College of MedicineChicagoUSA
  2. 2.Department of Math Statistics and Computer ScienceUIC College of Liberal Arts and SciencesChicagoUSA
  3. 3.Department of PharmacologyUIC College of MedicineChicagoUSA