Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting

Abstract Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAA...

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Autores principales: Daniela I. Staquicini, Roberto Rangel, Liliana Guzman-Rojas, Fernanda I. Staquicini, Andrey S. Dobroff, Christy A. Tarleton, Michelle A. Ozbun, Mikhail G. Kolonin, Juri G. Gelovani, Serena Marchiò, Richard L. Sidman, Katherine A. Hajjar, Wadih Arap, Renata Pasqualini
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Publicado: Nature Portfolio 2017
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spelling oai:doaj.org-article:5856840a50164afb9f65b36ea3d9f06a2021-12-02T12:32:50ZIntracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting10.1038/s41598-017-03470-w2045-2322https://doaj.org/article/5856840a50164afb9f65b36ea3d9f06a2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03470-whttps://doaj.org/toc/2045-2322Abstract Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG-pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protein kinase B (Akt). Likewise, tumor cells pretreated with LGRFYAASG-pen exhibited an impaired capacity to colonize the lungs in vivo in several mouse models. Together, our findings demonstrate an unrecognized functional link between intracellular annexin A2 and tumor cell adhesion, migration and in vivo grafting. Moreover, this work uncovers a new peptide motif that binds to and inhibits intracellular annexin A2 as a candidate therapeutic lead for potential translation into clinical applications.Daniela I. StaquiciniRoberto RangelLiliana Guzman-RojasFernanda I. StaquiciniAndrey S. DobroffChristy A. TarletonMichelle A. OzbunMikhail G. KoloninJuri G. GelovaniSerena MarchiòRichard L. SidmanKatherine A. HajjarWadih ArapRenata PasqualiniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Daniela I. Staquicini
Roberto Rangel
Liliana Guzman-Rojas
Fernanda I. Staquicini
Andrey S. Dobroff
Christy A. Tarleton
Michelle A. Ozbun
Mikhail G. Kolonin
Juri G. Gelovani
Serena Marchiò
Richard L. Sidman
Katherine A. Hajjar
Wadih Arap
Renata Pasqualini
Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting
description Abstract Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG-pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protein kinase B (Akt). Likewise, tumor cells pretreated with LGRFYAASG-pen exhibited an impaired capacity to colonize the lungs in vivo in several mouse models. Together, our findings demonstrate an unrecognized functional link between intracellular annexin A2 and tumor cell adhesion, migration and in vivo grafting. Moreover, this work uncovers a new peptide motif that binds to and inhibits intracellular annexin A2 as a candidate therapeutic lead for potential translation into clinical applications.
format article
author Daniela I. Staquicini
Roberto Rangel
Liliana Guzman-Rojas
Fernanda I. Staquicini
Andrey S. Dobroff
Christy A. Tarleton
Michelle A. Ozbun
Mikhail G. Kolonin
Juri G. Gelovani
Serena Marchiò
Richard L. Sidman
Katherine A. Hajjar
Wadih Arap
Renata Pasqualini
author_facet Daniela I. Staquicini
Roberto Rangel
Liliana Guzman-Rojas
Fernanda I. Staquicini
Andrey S. Dobroff
Christy A. Tarleton
Michelle A. Ozbun
Mikhail G. Kolonin
Juri G. Gelovani
Serena Marchiò
Richard L. Sidman
Katherine A. Hajjar
Wadih Arap
Renata Pasqualini
author_sort Daniela I. Staquicini
title Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting
title_short Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting
title_full Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting
title_fullStr Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting
title_full_unstemmed Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting
title_sort intracellular targeting of annexin a2 inhibits tumor cell adhesion, migration, and in vivo grafting
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/5856840a50164afb9f65b36ea3d9f06a
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