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Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells

Gill Conway Orcid Logo, Deimante Zizyte, Julie Rose Mae Mondala Orcid Logo, Zhonglei He, Lorna Lynam, Mathilde Lecourt Orcid Logo, Carlos Barcia, Orla Howe Orcid Logo, James F. Curtin Orcid Logo

Pharmaceuticals, Volume: 14, Issue: 2, Start page: 91

Swansea University Author: Gill Conway Orcid Logo

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DOI (Published version): 10.3390/ph14020091

Abstract

Ursolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM) and offers a promising starting point in drug discovery; however, understanding the relationship between...

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Published in: Pharmaceuticals
ISSN: 1424-8247
Published: MDPI AG 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa65437
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UA activates various signalling pathways in Glioblastoma multiforme (GBM) and offers a promising starting point in drug discovery; however, understanding the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrate that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM collective cell migration in a time dependent manner that is independent of the JNK signalling pathway. Cytotoxicity induced by UA results in the formation of acidic vesicle organelles (AVOs), speculating the activation of autophagy. However, inhibitor and spectrophotometric analysis demonstrated that autophagy was not responsible for the formation of the AVOs. Confocal microscopy and isosurface visualisation determined co-localisation of lysosomes with the previously identified AVOs, thus providing evidence that lysosomes are likely to be playing a role in UA induced cell death. 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spelling v2 65437 2024-01-10 Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells e33e0ee5a076ad91fe6615117caa1800 0000-0002-5991-0960 Gill Conway Gill Conway true false 2024-01-10 BMS Ursolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM) and offers a promising starting point in drug discovery; however, understanding the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrate that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM collective cell migration in a time dependent manner that is independent of the JNK signalling pathway. Cytotoxicity induced by UA results in the formation of acidic vesicle organelles (AVOs), speculating the activation of autophagy. However, inhibitor and spectrophotometric analysis demonstrated that autophagy was not responsible for the formation of the AVOs. Confocal microscopy and isosurface visualisation determined co-localisation of lysosomes with the previously identified AVOs, thus providing evidence that lysosomes are likely to be playing a role in UA induced cell death. Collectively, our data identify that UA rapidly induces a lysosomal associated mechanism of cell death in addition to UA acting as an inhibitor of GBM collective cell migration. Journal Article Pharmaceuticals 14 2 91 MDPI AG 1424-8247 ursolic acid; cell death; migration; lysosomes; nutraceuticals 26 1 2021 2021-01-26 10.3390/ph14020091 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University This work is supported by the Irish Research Council IRCSET grant (G.E.C), Spanish Ministry of Economy and Competitiveness and European Regional Development Fund Grant number SAF2015-64123-P (C.B. and G.P.C). 2024-03-21T11:32:28.1788970 2024-01-10T15:28:28.0770977 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Gill Conway 0000-0002-5991-0960 1 Deimante Zizyte 2 Julie Rose Mae Mondala 0000-0002-9656-311x 3 Zhonglei He 4 Lorna Lynam 5 Mathilde Lecourt 0000-0003-3552-2100 6 Carlos Barcia 7 Orla Howe 0000-0002-5150-022x 8 James F. Curtin 0000-0002-9320-9254 9 65437__29778__7d94900533f045329f8e17533eabf8d0.pdf 65437_VoR.pdf 2024-03-21T11:31:08.1474486 Output 3245866 application/pdf Version of Record true © 2021 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. true eng https://creativecommons.org/licenses/by/4.0/
title Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells
spellingShingle Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells
Gill Conway
title_short Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells
title_full Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells
title_fullStr Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells
title_full_unstemmed Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells
title_sort Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells
author_id_str_mv e33e0ee5a076ad91fe6615117caa1800
author_id_fullname_str_mv e33e0ee5a076ad91fe6615117caa1800_***_Gill Conway
author Gill Conway
author2 Gill Conway
Deimante Zizyte
Julie Rose Mae Mondala
Zhonglei He
Lorna Lynam
Mathilde Lecourt
Carlos Barcia
Orla Howe
James F. Curtin
format Journal article
container_title Pharmaceuticals
container_volume 14
container_issue 2
container_start_page 91
publishDate 2021
institution Swansea University
issn 1424-8247
doi_str_mv 10.3390/ph14020091
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Ursolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM) and offers a promising starting point in drug discovery; however, understanding the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrate that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM collective cell migration in a time dependent manner that is independent of the JNK signalling pathway. Cytotoxicity induced by UA results in the formation of acidic vesicle organelles (AVOs), speculating the activation of autophagy. However, inhibitor and spectrophotometric analysis demonstrated that autophagy was not responsible for the formation of the AVOs. Confocal microscopy and isosurface visualisation determined co-localisation of lysosomes with the previously identified AVOs, thus providing evidence that lysosomes are likely to be playing a role in UA induced cell death. Collectively, our data identify that UA rapidly induces a lysosomal associated mechanism of cell death in addition to UA acting as an inhibitor of GBM collective cell migration.
published_date 2021-01-26T11:32:25Z
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