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L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer
Recent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell—endothelial cell interaction and thus angiogenesis without cytotoxi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416969/ https://www.ncbi.nlm.nih.gov/pubmed/22333033 http://dx.doi.org/10.1111/j.1582-4934.2012.01547.x |
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author | Yu, Minshu Henning, Ryan Walker, Amanda Kim, Geoffrey Perroy, Alyssa Alessandro, Riccardo Virador, Victoria Kohn, Elise C |
author_facet | Yu, Minshu Henning, Ryan Walker, Amanda Kim, Geoffrey Perroy, Alyssa Alessandro, Riccardo Virador, Victoria Kohn, Elise C |
author_sort | Yu, Minshu |
collection | PubMed |
description | Recent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell—endothelial cell interaction and thus angiogenesis without cytotoxic effects. Ovarian cancer cell lines and human microvascular endothelial cells (HMVEC) were exposed to L-ASP at physiologically attainable concentrations and subjected to analyses of endothelial tube formation, invasion, adhesion and the assessment of sialylated proteins involved in matrix-associated and heterotypic cell adhesion. Marked reduction in HMVEC tube formation in vitro, HMVEC and ovarian cancer cell invasion, and heterotypic cell-cell and cell-matrix adhesion was observed (P < 0.05–0.0001). These effects were associated with reduced binding to ß1integrin, activation of FAK, and cell surface sialyl Lewis(X) (sLe(x)) expression. No reduction in HMVEC E-selectin expression was seen consistent with the unidirectional inhibitory actions observed. L-ASP concentrations were non-toxic to either ovarian cancer or HMVEC lines in the time frame of the assays. However, early changes of autophagy were observed in both cell types with induction of ATG12, beclin-1, and cleavage of LC-3, indicating cell injury did occur. These data and the known mechanism of action of L-ASP on glycosylation of nascent proteins suggest that L-ASP reduces of ovarian cancer dissemination and progression through modification of its microenvironment. The reduction of ovarian cancer cell surface sLe(x) inhibits interaction with HMVEC and thus HMVEC differentiation into tubes, inhibits interaction with the local matrix reducing invasive behaviour, and causes cell injury initiating autophagy in tumour and vascular cells. |
format | Online Article Text |
id | pubmed-3416969 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-34169692013-10-01 L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer Yu, Minshu Henning, Ryan Walker, Amanda Kim, Geoffrey Perroy, Alyssa Alessandro, Riccardo Virador, Victoria Kohn, Elise C J Cell Mol Med Original Articles Recent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell—endothelial cell interaction and thus angiogenesis without cytotoxic effects. Ovarian cancer cell lines and human microvascular endothelial cells (HMVEC) were exposed to L-ASP at physiologically attainable concentrations and subjected to analyses of endothelial tube formation, invasion, adhesion and the assessment of sialylated proteins involved in matrix-associated and heterotypic cell adhesion. Marked reduction in HMVEC tube formation in vitro, HMVEC and ovarian cancer cell invasion, and heterotypic cell-cell and cell-matrix adhesion was observed (P < 0.05–0.0001). These effects were associated with reduced binding to ß1integrin, activation of FAK, and cell surface sialyl Lewis(X) (sLe(x)) expression. No reduction in HMVEC E-selectin expression was seen consistent with the unidirectional inhibitory actions observed. L-ASP concentrations were non-toxic to either ovarian cancer or HMVEC lines in the time frame of the assays. However, early changes of autophagy were observed in both cell types with induction of ATG12, beclin-1, and cleavage of LC-3, indicating cell injury did occur. These data and the known mechanism of action of L-ASP on glycosylation of nascent proteins suggest that L-ASP reduces of ovarian cancer dissemination and progression through modification of its microenvironment. The reduction of ovarian cancer cell surface sLe(x) inhibits interaction with HMVEC and thus HMVEC differentiation into tubes, inhibits interaction with the local matrix reducing invasive behaviour, and causes cell injury initiating autophagy in tumour and vascular cells. Blackwell Publishing Ltd 2012-10 2012-09-26 /pmc/articles/PMC3416969/ /pubmed/22333033 http://dx.doi.org/10.1111/j.1582-4934.2012.01547.x Text en Copyright © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Original Articles Yu, Minshu Henning, Ryan Walker, Amanda Kim, Geoffrey Perroy, Alyssa Alessandro, Riccardo Virador, Victoria Kohn, Elise C L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer |
title | L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer |
title_full | L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer |
title_fullStr | L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer |
title_full_unstemmed | L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer |
title_short | L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer |
title_sort | l-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416969/ https://www.ncbi.nlm.nih.gov/pubmed/22333033 http://dx.doi.org/10.1111/j.1582-4934.2012.01547.x |
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