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PML Differentially Regulates Growth and Invasion in Brain Cancer

Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein...

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Autores principales: Tampakaki, Maria, Oraiopoulou, Mariam-Eleni, Tzamali, Eleftheria, Tzedakis, Giorgos, Makatounakis, Takis, Zacharakis, Giannis, Papamatheakis, Joseph, Sakkalis, Vangelis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230868/
https://www.ncbi.nlm.nih.gov/pubmed/34208139
http://dx.doi.org/10.3390/ijms22126289
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author Tampakaki, Maria
Oraiopoulou, Mariam-Eleni
Tzamali, Eleftheria
Tzedakis, Giorgos
Makatounakis, Takis
Zacharakis, Giannis
Papamatheakis, Joseph
Sakkalis, Vangelis
author_facet Tampakaki, Maria
Oraiopoulou, Mariam-Eleni
Tzamali, Eleftheria
Tzedakis, Giorgos
Makatounakis, Takis
Zacharakis, Giannis
Papamatheakis, Joseph
Sakkalis, Vangelis
author_sort Tampakaki, Maria
collection PubMed
description Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein (PML) in primary Glioblastoma samples. PML is implicated in various ways in cancer biology. In the brain, PML participates in the physiological migration of the neural progenitor cells, which have been hypothesized to serve as the cell of origin of Glioblastoma. The role of PML in Glioblastoma progression has recently gained attention due to its controversial effects in overall Glioblastoma evolution. In this work, we studied the role of PML in Glioblastoma pathophysiology using the U87MG cell line. We genetically modified the cells to conditionally overexpress the PML isoform IV and we focused on its dual role in tumor growth and invasive capacity. Furthermore, we targeted a PML action mediator, the Enhancer of Zeste Homolog 2 (EZH2), via the inhibitory drug DZNeP. We present a combined in vitro–in silico approach, that utilizes both 2D and 3D cultures and cancer-predictive computational algorithms, in order to differentiate and interpret the observed biological results. Our overall findings indicate that PML regulates growth and invasion through distinct cellular mechanisms. In particular, PML overexpression suppresses cell proliferation, while it maintains the invasive capacity of the U87MG Glioblastoma cells and, upon inhibition of the PML-EZH2 pathway, the invasion is drastically eliminated. Our in silico simulations suggest that the underlying mechanism of PML-driven Glioblastoma physiology regulates invasion by differential modulation of the cell-to-cell adhesive and diffusive capacity of the cells. Elucidating further the role of PML in Glioblastoma biology could set PML as a potential molecular biomarker of the tumor progression and its mediated pathway as a therapeutic target, aiming at inhibiting cell growth and potentially clonal evolution regarding their proliferative and/or invasive phenotype within the heterogeneous tumor mass.
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spelling pubmed-82308682021-06-26 PML Differentially Regulates Growth and Invasion in Brain Cancer Tampakaki, Maria Oraiopoulou, Mariam-Eleni Tzamali, Eleftheria Tzedakis, Giorgos Makatounakis, Takis Zacharakis, Giannis Papamatheakis, Joseph Sakkalis, Vangelis Int J Mol Sci Article Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein (PML) in primary Glioblastoma samples. PML is implicated in various ways in cancer biology. In the brain, PML participates in the physiological migration of the neural progenitor cells, which have been hypothesized to serve as the cell of origin of Glioblastoma. The role of PML in Glioblastoma progression has recently gained attention due to its controversial effects in overall Glioblastoma evolution. In this work, we studied the role of PML in Glioblastoma pathophysiology using the U87MG cell line. We genetically modified the cells to conditionally overexpress the PML isoform IV and we focused on its dual role in tumor growth and invasive capacity. Furthermore, we targeted a PML action mediator, the Enhancer of Zeste Homolog 2 (EZH2), via the inhibitory drug DZNeP. We present a combined in vitro–in silico approach, that utilizes both 2D and 3D cultures and cancer-predictive computational algorithms, in order to differentiate and interpret the observed biological results. Our overall findings indicate that PML regulates growth and invasion through distinct cellular mechanisms. In particular, PML overexpression suppresses cell proliferation, while it maintains the invasive capacity of the U87MG Glioblastoma cells and, upon inhibition of the PML-EZH2 pathway, the invasion is drastically eliminated. Our in silico simulations suggest that the underlying mechanism of PML-driven Glioblastoma physiology regulates invasion by differential modulation of the cell-to-cell adhesive and diffusive capacity of the cells. Elucidating further the role of PML in Glioblastoma biology could set PML as a potential molecular biomarker of the tumor progression and its mediated pathway as a therapeutic target, aiming at inhibiting cell growth and potentially clonal evolution regarding their proliferative and/or invasive phenotype within the heterogeneous tumor mass. MDPI 2021-06-11 /pmc/articles/PMC8230868/ /pubmed/34208139 http://dx.doi.org/10.3390/ijms22126289 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tampakaki, Maria
Oraiopoulou, Mariam-Eleni
Tzamali, Eleftheria
Tzedakis, Giorgos
Makatounakis, Takis
Zacharakis, Giannis
Papamatheakis, Joseph
Sakkalis, Vangelis
PML Differentially Regulates Growth and Invasion in Brain Cancer
title PML Differentially Regulates Growth and Invasion in Brain Cancer
title_full PML Differentially Regulates Growth and Invasion in Brain Cancer
title_fullStr PML Differentially Regulates Growth and Invasion in Brain Cancer
title_full_unstemmed PML Differentially Regulates Growth and Invasion in Brain Cancer
title_short PML Differentially Regulates Growth and Invasion in Brain Cancer
title_sort pml differentially regulates growth and invasion in brain cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230868/
https://www.ncbi.nlm.nih.gov/pubmed/34208139
http://dx.doi.org/10.3390/ijms22126289
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