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

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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.

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Acknowledgments

This work was supported through a Sponsored Research Agreement between CDG Therapeutics, Inc., and the University of Illinois at Chicago (UIC). All terms of the Sponsored Research Agreements are managed by UIC in accordance with its conflict of interest management policies.

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Authors and Affiliations

  1. Department of Surgery, Division of Surgical Oncology, UIC College of Medicine, 618 CSB MC 820, 840 South Wood Street, Chicago, IL, 60612, USA

    Rajeshwari R. Mehta, Tohru Yamada, Brad N. Taylor, Konstantin Christov, Fatima Lekmine, Anne Shilkaitis, Laura Bratescu, Albert Green, Craig W. Beattie & Tapas K. Das Gupta

  2. Department of Math Statistics and Computer Science, UIC College of Liberal Arts and Sciences, 322 SEO MC 249, 851 S. Morgan Street, Chicago, IL, 60607, USA

    Marissa L. King & Dibyen Majumdar

  3. Department of Pharmacology, UIC College of Medicine, E403 MSB MC 868, 835 S. Wolcott, Chicago, IL, 60612, USA

    Chinnaswamy Tiruppathi

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  1. Rajeshwari R. Mehta
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  2. Tohru Yamada
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Correspondence to Tapas K. Das Gupta.

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Rajeshwari R. Mehta and Tohru Yamada contributed equally to this research.

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Mehta, R.R., Yamada, T., Taylor, B.N. et al. A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2, FAK and Akt. Angiogenesis 14, 355–369 (2011). https://doi.org/10.1007/s10456-011-9220-6

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  • DOI: https://doi.org/10.1007/s10456-011-9220-6

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