Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yu, Minshu, Henning, Ryan, Walker, Amanda, Kim, Geoffrey, Perroy, Alyssa, Alessandro, Riccardo, Virador, Victoria, Kohn, Elise C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2012
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
_version_ 1782240469894299648
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
work_keys_str_mv AT yuminshu lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer
AT henningryan lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer
AT walkeramanda lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer
AT kimgeoffrey lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer
AT perroyalyssa lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer
AT alessandroriccardo lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer
AT viradorvictoria lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer
AT kohnelisec lasparaginaseinhibitsinvasiveandangiogenicactivityandinducesautophagyinovariancancer