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Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

The anticancer effect of L-asparaginases (L-ASNases) is attributable to their ability to hydrolyze L-asparagine in the bloodstream and cancer cell microenvironment. Rhodospirillum rubrum (RrA) has dual mechanism of action and plays a role in the suppression of telomerase activity. The aim of this wo...

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Autores principales: Plyasova, Anna A., Pokrovskaya, Marina V., Lisitsyna, Olga M., Pokrovsky, Vadim S., Alexandrova, Svetlana S., Hilal, Abdullah, Sokolov, Nikolay N., Zhdanov, Dmitry D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650658/
https://www.ncbi.nlm.nih.gov/pubmed/33008089
http://dx.doi.org/10.3390/ph13100286
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author Plyasova, Anna A.
Pokrovskaya, Marina V.
Lisitsyna, Olga M.
Pokrovsky, Vadim S.
Alexandrova, Svetlana S.
Hilal, Abdullah
Sokolov, Nikolay N.
Zhdanov, Dmitry D.
author_facet Plyasova, Anna A.
Pokrovskaya, Marina V.
Lisitsyna, Olga M.
Pokrovsky, Vadim S.
Alexandrova, Svetlana S.
Hilal, Abdullah
Sokolov, Nikolay N.
Zhdanov, Dmitry D.
author_sort Plyasova, Anna A.
collection PubMed
description The anticancer effect of L-asparaginases (L-ASNases) is attributable to their ability to hydrolyze L-asparagine in the bloodstream and cancer cell microenvironment. Rhodospirillum rubrum (RrA) has dual mechanism of action and plays a role in the suppression of telomerase activity. The aim of this work was to investigate the possible mechanism of RrA penetration into human cancer cells. Labeling of widely used L-ASNases by fluorescein isothiocyanate followed by flow cytometry and fluorescent microscopy demonstrated that only RrA can interact with cell membranes. The screening of inhibitors of receptor-mediated endocytosis demonstrated the involvement of clathrin receptors in RrA penetration into cells. Confocal microscopy confirmed the cytoplasmic and nuclear localization of RrA in human breast cancer SKBR3 cells. Two predicted nuclear localization motifs allow RrA to penetrate into the cell nucleus and inhibit telomerase. Chromatin relaxation promoted by different agents can increase the ability of RrA to suppress the expression of telomerase main catalytic subunit. Our study demonstrated for the first time the ability of RrA to penetrate into human cancer cells and the involvement of clathrin receptors in this process.
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spelling pubmed-76506582020-11-10 Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase Plyasova, Anna A. Pokrovskaya, Marina V. Lisitsyna, Olga M. Pokrovsky, Vadim S. Alexandrova, Svetlana S. Hilal, Abdullah Sokolov, Nikolay N. Zhdanov, Dmitry D. Pharmaceuticals (Basel) Article The anticancer effect of L-asparaginases (L-ASNases) is attributable to their ability to hydrolyze L-asparagine in the bloodstream and cancer cell microenvironment. Rhodospirillum rubrum (RrA) has dual mechanism of action and plays a role in the suppression of telomerase activity. The aim of this work was to investigate the possible mechanism of RrA penetration into human cancer cells. Labeling of widely used L-ASNases by fluorescein isothiocyanate followed by flow cytometry and fluorescent microscopy demonstrated that only RrA can interact with cell membranes. The screening of inhibitors of receptor-mediated endocytosis demonstrated the involvement of clathrin receptors in RrA penetration into cells. Confocal microscopy confirmed the cytoplasmic and nuclear localization of RrA in human breast cancer SKBR3 cells. Two predicted nuclear localization motifs allow RrA to penetrate into the cell nucleus and inhibit telomerase. Chromatin relaxation promoted by different agents can increase the ability of RrA to suppress the expression of telomerase main catalytic subunit. Our study demonstrated for the first time the ability of RrA to penetrate into human cancer cells and the involvement of clathrin receptors in this process. MDPI 2020-09-30 /pmc/articles/PMC7650658/ /pubmed/33008089 http://dx.doi.org/10.3390/ph13100286 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Plyasova, Anna A.
Pokrovskaya, Marina V.
Lisitsyna, Olga M.
Pokrovsky, Vadim S.
Alexandrova, Svetlana S.
Hilal, Abdullah
Sokolov, Nikolay N.
Zhdanov, Dmitry D.
Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase
title Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase
title_full Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase
title_fullStr Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase
title_full_unstemmed Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase
title_short Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase
title_sort penetration into cancer cells via clathrin-dependent mechanism allows l-asparaginase from rhodospirillum rubrum to inhibit telomerase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650658/
https://www.ncbi.nlm.nih.gov/pubmed/33008089
http://dx.doi.org/10.3390/ph13100286
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