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Targeting tumor cell invasion and dissemination in vivo by an aptamer that inhibits urokinase-type plasminogen activator through a novel multifunctional mechanism

Academic Article
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Overview

authors

  • Botkjaer, K. A.
  • Deryugina, Elena
  • Dupont, D. M.
  • Gardsvoll, H.
  • Bekes, E. M.
  • Thuesen, C. K.
  • Chen, Z.
  • Ploug, M.
  • Quigley, James
  • Andreasen, P. A.

publication date

  • December 2012

journal

  • Molecular Cancer Research  Journal

abstract

  • Data accumulated over the latest two decades have established that the serine protease urokinase-type plasminogen activator (uPA) is a potential therapeutic target in cancer. When designing inhibitors of the proteolytic activity of serine proteases, obtaining sufficient specificity is problematic, because the topology of the proteases' active sites are highly similar. In an effort to generate highly specific uPA inhibitors with new inhibitory modalities, we isolated uPA-binding RNA aptamers by screening a library of 35 nucleotides long 2'-fluoro-pyrimidine RNA molecules using a version of human pro-uPA lacking the epidermal growth factor-like and kringle domains as bait. One pro-uPA-binding aptamer sequence, referred to as upanap-126, proved to be highly specific for human uPA. Upanap-126 delayed the proteolytic conversion of human pro-uPA to active uPA, but did not inhibit plasminogen activation catalyzed by two-chain uPA. The aptamer also inhibited the binding of pro-uPA to uPAR and the binding of vitronectin to the preformed pro-uPA/uPAR complex, both in cell-free systems and on cell surfaces. Furthermore, upanap-126 inhibited human tumor cell invasion in vitro in the Matrigel assay and in vivo in the chick embryo assay of cell escape from microtumors. Finally, upanap-126 significantly reduced the levels of tumor cell intravasation and dissemination in the chick embryo model of spontaneous metastasis. Together, our findings show that usage of upanap-126 represents a novel multifunctional mechanistic modality for inhibition of uPA-dependent processes involved in tumor cell spread.

subject areas

  • Animals
  • Aptamers, Nucleotide
  • Cell Line, Tumor
  • Cell-Free System
  • Chick Embryo
  • Epidermal Growth Factor
  • HEK293 Cells
  • Humans
  • Male
  • Molecular Targeted Therapy
  • Neoplasm Invasiveness
  • Plasminogen
  • Prostatic Neoplasms
  • Recombinant Proteins
  • Serine Proteases
  • Urokinase-Type Plasminogen Activator
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Identity

PubMed Central ID

  • PMC3528818

International Standard Serial Number (ISSN)

  • 1541-7786

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.mcr-12-0349

PubMed ID

  • 23038812
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Additional Document Info

start page

  • 1532

end page

  • 1543

volume

  • 10

issue

  • 12

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