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Fröhlich, LF; Mrakovcic, M; Smole, C; Lahiri, P; Zatloukal, K.
Epigenetic silencing of apoptosis-inducing gene expression can be efficiently overcome by combined SAHA and TRAIL treatment in uterine sarcoma cells.
PLoS One. 2014; 9(3):e91558-e91558 Doi: 10.1371/journal.pone.0091558 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Fröhlich Leopold F.
Fröhlich Maria
Co-Autor*innen der Med Uni Graz
Lahiri Pooja
Smole Claudia
Zatloukal Kurt

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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.
Find related publications in this database (using NLM MeSH Indexing)
Apoptosis - genetics
Caspase 3 - metabolism
Caspase 8 - genetics
Caspase 8 - metabolism
Cell Line, Tumor -
DNA Methylation -
Drug Resistance, Neoplasm - genetics
Drug Synergism -
Enzyme Activation - drug effects
Epigenesis, Genetic -
Female -
Gene Expression Regulation, Neoplastic -
Gene Transfer Techniques -
Histone Deacetylase Inhibitors -
Humans -
Hydroxamic Acids - pharmacology
Hydroxamic Acids - toxicity
Membrane Potential, Mitochondrial -
Mitochondria - drug effects
Mitochondria - metabolism
Promoter Regions, Genetic -
Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
Sarcoma - genetics
TNF-Related Apoptosis-Inducing Ligand - pharmacology
TNF-Related Apoptosis-Inducing Ligand - toxicity
Uterine Neoplasms - genetics

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