Document Detail


Targeting tumor cell invasion and dissemination in vivo by an aptamer that inhibits urokinase-type plasminogen activator through a novel multifunctional mechanism.
MedLine Citation:
PMID:  23038812     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kenneth A Botkjaer; Elena I Deryugina; Daniel M Dupont; Henrik Gårdsvoll; Erin M Bekes; Cathrine K Thuesen; Zhuo Chen; Zhou Chen; Michael Ploug; James P Quigley; Peter A Andreasen
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-04
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  10     ISSN:  1557-3125     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-21     Completed Date:  2013-09-03     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1532-43     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Aptamers, Nucleotide / genetics*,  pharmacology*
Cell Line, Tumor
Cell-Free System
Chick Embryo
Epidermal Growth Factor / genetics,  metabolism
HEK293 Cells
Humans
Male
Molecular Targeted Therapy
Neoplasm Invasiveness
Plasminogen / genetics,  metabolism
Prostatic Neoplasms / genetics,  metabolism,  pathology*,  therapy*
Recombinant Proteins / genetics,  metabolism
Serine Proteases / genetics,  metabolism
Urokinase-Type Plasminogen Activator / antagonists & inhibitors*,  genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
5T 32CA077109/CA/NCI NIH HHS; R01 CA 105412/CA/NCI NIH HHS; R01 CA 129484/CA/NCI NIH HHS; R01 CA105412/CA/NCI NIH HHS; R01 CA129484/CA/NCI NIH HHS; T32 CA077109/CA/NCI NIH HHS; UL1 RR025774/RR/NCRR NIH HHS; UL1 RR025774/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Aptamers, Nucleotide; 0/Recombinant Proteins; 62229-50-9/Epidermal Growth Factor; 9001-91-6/Plasminogen; 99149-95-8/saruplase; EC 3.4.-/Serine Proteases; EC 3.4.21.73/Urokinase-Type Plasminogen Activator
Comments/Corrections
Erratum In:
Mol Cancer Res. 2013 Aug;11(8):964
Note: Chen, Zhou [corrected to Chen, Zhuo]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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