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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Published in:PloS one 2014-03, Vol.9 (3), p.e91558
Main Authors: Fröhlich, Leopold F, Mrakovcic, Maria, Smole, Claudia, Lahiri, Pooja, Zatloukal, Kurt
Format: Article
Language:English
Subjects:
5-aza-2'-deoxycytidine
Acetylation
Apoptosis
Apoptosis - genetics
Biology
Biotechnology
Caspase
Caspase 3 - metabolism
Caspase 8 - genetics
Caspase 8 - metabolism
Caspase-3
Caspase-8
Cell death
Cell Line, Tumor
Combinatorial analysis
Combined treatment
Cytotoxicity
Deoxyribonucleic acid
Deregulation
DNA
DNA Methylation
Drug Resistance, Neoplasm - genetics
Drug Synergism
Enzyme Activation - drug effects
Epigenesis, Genetic
Epigenetic inheritance
Female
Gene expression
Gene Expression Regulation, Neoplastic
Gene sequencing
Gene transfer
Gene Transfer Techniques
Genes
Genetic engineering
Health aspects
Histone deacetylase
Histone Deacetylase Inhibitors
Humans
Hydroxamic acid
Hydroxamic Acids - pharmacology
Hydroxamic Acids - toxicity
Medicine
Membrane potential
Membrane Potential, Mitochondrial
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Molecular modelling
Nucleotide sequence
Poly(ADP-ribose) polymerase
Promoter Regions, Genetic
Promoters (Genetics)
Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
Sarcoma
Sarcoma - genetics
TNF-Related Apoptosis-Inducing Ligand - pharmacology
TNF-Related Apoptosis-Inducing Ligand - toxicity
TRAIL protein
Tumor cell lines
Tumor necrosis factor
Tumors
Uterine cancer
Uterine Neoplasms - genetics
Uterus
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0091558