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Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells

The lack of knowledge about molecular pathology of uterine sarcomas with a representation of 3–7% of all malignant uterine tumors prevents the establishment of effective therapy protocols. Here, we explored advanced therapeutic options to the previously discovered antitumorigenic effects of the hist...

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Autores principales: Fröhlich, Leopold F., Mrakovcic, Maria, Smole, Claudia, Lahiri, Pooja, Zatloukal, Kurt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950220/
https://www.ncbi.nlm.nih.gov/pubmed/24618889
http://dx.doi.org/10.1371/journal.pone.0091558
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author Fröhlich, Leopold F.
Mrakovcic, Maria
Smole, Claudia
Lahiri, Pooja
Zatloukal, Kurt
author_facet Fröhlich, Leopold F.
Mrakovcic, Maria
Smole, Claudia
Lahiri, Pooja
Zatloukal, Kurt
author_sort Fröhlich, Leopold F.
collection PubMed
description The lack of knowledge about molecular pathology of uterine sarcomas with a representation of 3–7% of all malignant uterine tumors prevents the establishment of effective therapy protocols. Here, we explored advanced therapeutic options to the previously discovered antitumorigenic effects of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) by combined treatment with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L). In addition, we investigated the uterine sarcoma cell lines, MES-SA and ESS-1, regarding the underlying molecular mechanisms of SAHA and TRAIL-induced apoptosis and their resistance towards TRAIL. Compared to single SAHA or TRAIL treatment, the combination of SAHA with TRAIL led to complete cell death of both tumor cell lines after 24 to 48 hours. In contrast to single SAHA treatment, apoptosis occured faster and was more pronounced in ESS-1 cells than in MES-SA cells. Induction of SAHA- and TRAIL-induced apoptosis was accompanied by upregulation of the intrinsic apoptotic pathway via reduction of mitochondrial membrane potential, caspase-3, -6, and -7 activation, and PARP cleavage, but was also found to be partially caspase-independent. Apoptosis resistance was caused by reduced expression of caspase-8 and DR 4/TRAIL-R1 in ESS-1 and MES-SA cells, respectively, due to epigenetic silencing by DNA hypermethylation of gene promoter sequences. Treatment with the demethylating agent 5-Aza-2'-deoxycytidine or gene transfer therefore restored gene expression and increased the sensitivity of both cell lines against TRAIL-induced apoptosis. Our data provide evidence that deregulation of epigenetic silencing by histone acetylation and DNA hypermethylation might play a fundamental role in the origin of uterine sarcomas. Therefore, tumor growth might be efficiently overcome by a cytotoxic combinatorial treatment of HDAC inhibitors with TRAIL.
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spelling pubmed-39502202014-03-12 Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells Fröhlich, Leopold F. Mrakovcic, Maria Smole, Claudia Lahiri, Pooja Zatloukal, Kurt PLoS One Research Article The lack of knowledge about molecular pathology of uterine sarcomas with a representation of 3–7% of all malignant uterine tumors prevents the establishment of effective therapy protocols. Here, we explored advanced therapeutic options to the previously discovered antitumorigenic effects of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) by combined treatment with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L). In addition, we investigated the uterine sarcoma cell lines, MES-SA and ESS-1, regarding the underlying molecular mechanisms of SAHA and TRAIL-induced apoptosis and their resistance towards TRAIL. Compared to single SAHA or TRAIL treatment, the combination of SAHA with TRAIL led to complete cell death of both tumor cell lines after 24 to 48 hours. In contrast to single SAHA treatment, apoptosis occured faster and was more pronounced in ESS-1 cells than in MES-SA cells. Induction of SAHA- and TRAIL-induced apoptosis was accompanied by upregulation of the intrinsic apoptotic pathway via reduction of mitochondrial membrane potential, caspase-3, -6, and -7 activation, and PARP cleavage, but was also found to be partially caspase-independent. Apoptosis resistance was caused by reduced expression of caspase-8 and DR 4/TRAIL-R1 in ESS-1 and MES-SA cells, respectively, due to epigenetic silencing by DNA hypermethylation of gene promoter sequences. Treatment with the demethylating agent 5-Aza-2'-deoxycytidine or gene transfer therefore restored gene expression and increased the sensitivity of both cell lines against TRAIL-induced apoptosis. Our data provide evidence that deregulation of epigenetic silencing by histone acetylation and DNA hypermethylation might play a fundamental role in the origin of uterine sarcomas. Therefore, tumor growth might be efficiently overcome by a cytotoxic combinatorial treatment of HDAC inhibitors with TRAIL. Public Library of Science 2014-03-11 /pmc/articles/PMC3950220/ /pubmed/24618889 http://dx.doi.org/10.1371/journal.pone.0091558 Text en © 2014 Fröhlich et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Fröhlich, Leopold F.
Mrakovcic, Maria
Smole, Claudia
Lahiri, Pooja
Zatloukal, Kurt
Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells
title Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells
title_full Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells
title_fullStr Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells
title_full_unstemmed Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells
title_short Epigenetic Silencing of Apoptosis-Inducing Gene Expression Can Be Efficiently Overcome by Combined SAHA and TRAIL Treatment in Uterine Sarcoma Cells
title_sort epigenetic silencing of apoptosis-inducing gene expression can be efficiently overcome by combined saha and trail treatment in uterine sarcoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950220/
https://www.ncbi.nlm.nih.gov/pubmed/24618889
http://dx.doi.org/10.1371/journal.pone.0091558
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