Cargando…

Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death

Osteosarcoma (OS) is one of the most malignant tumors of childhood and adolescence. Research on mitochondrial dynamics (fusion/fission) and biogenesis has received much attention in last few years, as they are crucial for death of cancer cells. Specifically, it was shown that increased expression of...

Descripción completa

Detalles Bibliográficos
Autores principales: Gorska-Ponikowska, Magdalena, Bastian, Paulina, Zauszkiewicz-Pawlak, Agata, Ploska, Agata, Zubrzycki, Adrian, Kuban-Jankowska, Alicja, Nussberger, Stephan, Kalinowski, Leszek, Kmiec, Zbigniew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811003/
https://www.ncbi.nlm.nih.gov/pubmed/33452331
http://dx.doi.org/10.1038/s41598-020-80816-x
_version_ 1783637418244571136
author Gorska-Ponikowska, Magdalena
Bastian, Paulina
Zauszkiewicz-Pawlak, Agata
Ploska, Agata
Zubrzycki, Adrian
Kuban-Jankowska, Alicja
Nussberger, Stephan
Kalinowski, Leszek
Kmiec, Zbigniew
author_facet Gorska-Ponikowska, Magdalena
Bastian, Paulina
Zauszkiewicz-Pawlak, Agata
Ploska, Agata
Zubrzycki, Adrian
Kuban-Jankowska, Alicja
Nussberger, Stephan
Kalinowski, Leszek
Kmiec, Zbigniew
author_sort Gorska-Ponikowska, Magdalena
collection PubMed
description Osteosarcoma (OS) is one of the most malignant tumors of childhood and adolescence. Research on mitochondrial dynamics (fusion/fission) and biogenesis has received much attention in last few years, as they are crucial for death of cancer cells. Specifically, it was shown that increased expression of the cytoplasmic dynamin-related protein 1 (Drp1) triggers mitochondrial fission (division), which activates BAX and downstream intrinsic apoptosis, effectively inhibiting OS growth. In the presented study, human OS cells (metastatic 143B OS cell line) were incubated with 2-methoxyestradiol (2-ME) at both physiologically and pharmacologically relevant concentrations. Cell viability was determined by the MTT assay. Confocal microscopy and western blot methods were applied to examine changes in Drp1 and BAX protein levels. Mitochondrial Division Inhibitor 1, MDIVI-1, was used in the study to further examine the role of Drp1 in 2-ME-mediated mechanism of action. To determine quantitative and qualitative changes in mitochondria, electron microscopy was used. 2-ME at all used concentrations increased mitochondrial fission and induced autophagy in OS cells. At the concentration of 1 µM 2-ME increased the area density of mitochondria in OS cells. Subsequent, upregulated expression of Drp1 and BAX proteins by 2-ME strongly suggests the activation of the intrinsic apoptosis pathway. We further observed 2-ME-mediated regulation of glycolytic state of OS cells. Therefore, we suggest that changes of mitochondrial dynamics may represent a novel mechanism of anticancer action of 2-ME. This finding may open new approaches to improve the efficacy of chemotherapy in the treatment of OS, however, it has to be confirmed by in vivo studies.
format Online
Article
Text
id pubmed-7811003
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-78110032021-01-21 Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death Gorska-Ponikowska, Magdalena Bastian, Paulina Zauszkiewicz-Pawlak, Agata Ploska, Agata Zubrzycki, Adrian Kuban-Jankowska, Alicja Nussberger, Stephan Kalinowski, Leszek Kmiec, Zbigniew Sci Rep Article Osteosarcoma (OS) is one of the most malignant tumors of childhood and adolescence. Research on mitochondrial dynamics (fusion/fission) and biogenesis has received much attention in last few years, as they are crucial for death of cancer cells. Specifically, it was shown that increased expression of the cytoplasmic dynamin-related protein 1 (Drp1) triggers mitochondrial fission (division), which activates BAX and downstream intrinsic apoptosis, effectively inhibiting OS growth. In the presented study, human OS cells (metastatic 143B OS cell line) were incubated with 2-methoxyestradiol (2-ME) at both physiologically and pharmacologically relevant concentrations. Cell viability was determined by the MTT assay. Confocal microscopy and western blot methods were applied to examine changes in Drp1 and BAX protein levels. Mitochondrial Division Inhibitor 1, MDIVI-1, was used in the study to further examine the role of Drp1 in 2-ME-mediated mechanism of action. To determine quantitative and qualitative changes in mitochondria, electron microscopy was used. 2-ME at all used concentrations increased mitochondrial fission and induced autophagy in OS cells. At the concentration of 1 µM 2-ME increased the area density of mitochondria in OS cells. Subsequent, upregulated expression of Drp1 and BAX proteins by 2-ME strongly suggests the activation of the intrinsic apoptosis pathway. We further observed 2-ME-mediated regulation of glycolytic state of OS cells. Therefore, we suggest that changes of mitochondrial dynamics may represent a novel mechanism of anticancer action of 2-ME. This finding may open new approaches to improve the efficacy of chemotherapy in the treatment of OS, however, it has to be confirmed by in vivo studies. Nature Publishing Group UK 2021-01-15 /pmc/articles/PMC7811003/ /pubmed/33452331 http://dx.doi.org/10.1038/s41598-020-80816-x Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gorska-Ponikowska, Magdalena
Bastian, Paulina
Zauszkiewicz-Pawlak, Agata
Ploska, Agata
Zubrzycki, Adrian
Kuban-Jankowska, Alicja
Nussberger, Stephan
Kalinowski, Leszek
Kmiec, Zbigniew
Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death
title Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death
title_full Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death
title_fullStr Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death
title_full_unstemmed Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death
title_short Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death
title_sort regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811003/
https://www.ncbi.nlm.nih.gov/pubmed/33452331
http://dx.doi.org/10.1038/s41598-020-80816-x
work_keys_str_mv AT gorskaponikowskamagdalena regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT bastianpaulina regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT zauszkiewiczpawlakagata regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT ploskaagata regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT zubrzyckiadrian regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT kubanjankowskaalicja regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT nussbergerstephan regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT kalinowskileszek regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath
AT kmieczbigniew regulationofmitochondrialdynamicsin2methoxyestradiolmediatedosteosarcomacelldeath