Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding

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Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding. / Dupont, Daniel Miotto; Madsen, Jeppe Buur; Hartmann, Roland Karl; Tavitian, Bertrand; Ducongé, Frédéric; Kjems, Jørgen; Andreasen, Peter André.

I: RNA, Bind 16, Nr. 12, 01.12.2010, s. 2360-9.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Dupont, Daniel Miotto ; Madsen, Jeppe Buur ; Hartmann, Roland Karl ; Tavitian, Bertrand ; Ducongé, Frédéric ; Kjems, Jørgen ; Andreasen, Peter André. / Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding. I: RNA. 2010 ; Bind 16, Nr. 12. s. 2360-9.

Bibtex

@article{9f6ad7badec84285a67d1c1a4b09d3a4,
title = "Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding",
abstract = "The serine proteinase urokinase-type plasminogen activator (uPA) is widely recognized as a potential target for anticancer therapy. Its association with cell surfaces through the uPA receptor (uPAR) is central to its function and plays an important role in cancer invasion and metastasis. In the current study, we used systematic evolution of ligands by exponential enrichment (SELEX) to select serum-stable 2'-fluoro-pyrimidine-modified RNA aptamers specifically targeting human uPA and blocking the interaction to its receptor at low nanomolar concentrations. In agreement with the inhibitory function of the aptamers, binding was found to be dependent on the presence of the growth factor domain of uPA, which mediates uPAR binding. One of the most potent uPA aptamers, upanap-12, was analyzed in more detail and could be reduced significantly in size without severe loss of its inhibitory activity. Finally, we show that the uPA-scavenging effect of the aptamers can reduce uPAR-dependent endocytosis of the uPA-PAI-1 complex and cell-surface associated plasminogen activation in cell culture experiments. uPA-scavenging 2'-fluoro-pyrimidine-modified RNA aptamers represent a novel promising principle for interfering with the pathological functions of the uPA system.",
keywords = "Antineoplastic Agents, Aptamers, Nucleotide, Base Sequence, Drug Screening Assays, Antitumor, Drug Stability, Endocytosis, Humans, Molecular Sequence Data, Multiprotein Complexes, Plasminogen Activator Inhibitor 1, Protein Binding, Protein Structure, Tertiary, Receptors, Urokinase Plasminogen Activator, Serum, Substrate Specificity, Urokinase-Type Plasminogen Activator",
author = "Dupont, {Daniel Miotto} and Madsen, {Jeppe Buur} and Hartmann, {Roland Karl} and Bertrand Tavitian and Fr{\'e}d{\'e}ric Ducong{\'e} and J{\o}rgen Kjems and Andreasen, {Peter Andr{\'e}}",
year = "2010",
month = dec,
day = "1",
doi = "10.1261/rna.2338210",
language = "English",
volume = "16",
pages = "2360--9",
journal = "RNA",
issn = "1355-8382",
publisher = "Cold Spring Harbor Laboratory Press",
number = "12",

}

RIS

TY - JOUR

T1 - Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding

AU - Dupont, Daniel Miotto

AU - Madsen, Jeppe Buur

AU - Hartmann, Roland Karl

AU - Tavitian, Bertrand

AU - Ducongé, Frédéric

AU - Kjems, Jørgen

AU - Andreasen, Peter André

PY - 2010/12/1

Y1 - 2010/12/1

N2 - The serine proteinase urokinase-type plasminogen activator (uPA) is widely recognized as a potential target for anticancer therapy. Its association with cell surfaces through the uPA receptor (uPAR) is central to its function and plays an important role in cancer invasion and metastasis. In the current study, we used systematic evolution of ligands by exponential enrichment (SELEX) to select serum-stable 2'-fluoro-pyrimidine-modified RNA aptamers specifically targeting human uPA and blocking the interaction to its receptor at low nanomolar concentrations. In agreement with the inhibitory function of the aptamers, binding was found to be dependent on the presence of the growth factor domain of uPA, which mediates uPAR binding. One of the most potent uPA aptamers, upanap-12, was analyzed in more detail and could be reduced significantly in size without severe loss of its inhibitory activity. Finally, we show that the uPA-scavenging effect of the aptamers can reduce uPAR-dependent endocytosis of the uPA-PAI-1 complex and cell-surface associated plasminogen activation in cell culture experiments. uPA-scavenging 2'-fluoro-pyrimidine-modified RNA aptamers represent a novel promising principle for interfering with the pathological functions of the uPA system.

AB - The serine proteinase urokinase-type plasminogen activator (uPA) is widely recognized as a potential target for anticancer therapy. Its association with cell surfaces through the uPA receptor (uPAR) is central to its function and plays an important role in cancer invasion and metastasis. In the current study, we used systematic evolution of ligands by exponential enrichment (SELEX) to select serum-stable 2'-fluoro-pyrimidine-modified RNA aptamers specifically targeting human uPA and blocking the interaction to its receptor at low nanomolar concentrations. In agreement with the inhibitory function of the aptamers, binding was found to be dependent on the presence of the growth factor domain of uPA, which mediates uPAR binding. One of the most potent uPA aptamers, upanap-12, was analyzed in more detail and could be reduced significantly in size without severe loss of its inhibitory activity. Finally, we show that the uPA-scavenging effect of the aptamers can reduce uPAR-dependent endocytosis of the uPA-PAI-1 complex and cell-surface associated plasminogen activation in cell culture experiments. uPA-scavenging 2'-fluoro-pyrimidine-modified RNA aptamers represent a novel promising principle for interfering with the pathological functions of the uPA system.

KW - Antineoplastic Agents

KW - Aptamers, Nucleotide

KW - Base Sequence

KW - Drug Screening Assays, Antitumor

KW - Drug Stability

KW - Endocytosis

KW - Humans

KW - Molecular Sequence Data

KW - Multiprotein Complexes

KW - Plasminogen Activator Inhibitor 1

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Receptors, Urokinase Plasminogen Activator

KW - Serum

KW - Substrate Specificity

KW - Urokinase-Type Plasminogen Activator

U2 - 10.1261/rna.2338210

DO - 10.1261/rna.2338210

M3 - Journal article

C2 - 20962041

VL - 16

SP - 2360

EP - 2369

JO - RNA

JF - RNA

SN - 1355-8382

IS - 12

ER -