Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Hrzenjak, A; Kremser, ML; Strohmeier, B; Moinfar, F; Zatloukal, K; Denk, H.
SAHA induces caspase-independent, autophagic cell death of endometrial stromal sarcoma cells by influencing the mTOR pathway.
J Pathol. 2008; 216(4):495-504
Doi: 10.1002/path.2434
Web of Science
PubMed
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FullText_MUG
- Leading authors Med Uni Graz
- Hrzenjak Andelko
- Co-authors Med Uni Graz
- Denk Helmut
- Kremser Maria-Luise
- Moinfar Farid
- Siebenhandl Bettina
- Zatloukal Kurt
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- Abstract:
- Endometrial stromal sarcomas are rare and molecular mechanisms involved in their pathogenesis are poorly understood. Covalent modifications of histone proteins, in particular de/acetylation of lysine residues, play an important role in the regulation of gene transcription in normal and neoplastic cells, but there are only limited data about these processes in solid mesenchymal tumours. We treated endometrial stromal sarcoma cells (ESS-1) and non-malignant human endometrial stromal cells (HESCs) with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. SAHA was able to mediate the cell cycle and expression of genes related to the malignant phenotype of endometrial stromal tumours, eg p21(WAF1) and HDAC7. SAHA led to dose-dependent differentiation and death of ESS-1 cells but not of HESCs. Exposure of HESCs to SAHA resulted only in slightly decreased cell proliferation. SAHA also increased the p21(WAF1) expression and caused significant changes in the cell cycle by inhibiting the G1/S transition in ESS-1 cells. Recovery experiments indicated that these changes became irreversible when the tumour cells were treated with SAHA for longer than 24 h. In our experimental system, not apoptotic but autophagic processes were responsible for the cell death. Monodansyl cadaverine accumulation in treated ESS-1 cells and decreased expression of the mTOR and phospho-S6 ribosomal protein (S6rp) additionally supported this observation. Taken together, our study indicates that HDACs might be considered as potential drug targets in the therapy of stromal sarcomas and that SAHA might be a promising therapeutic agent for endometrial stromal sarcoma.
- Find related publications in this database (using NLM MeSH Indexing)
- Autophagy - drug effects
- Cell Cycle - drug effects
- Cell Line, Tumor -
- Cell Proliferation - drug effects
- Cyclin-Dependent Kinase Inhibitor p21 - metabolism
- Endometrial Neoplasms - drug therapy
- Endometrial Neoplasms - pathology
- Enzyme Inhibitors - therapeutic use
- Female -
- Histone Deacetylase Inhibitors -
- Histone Deacetylases - metabolism
- Humans -
- Hydroxamic Acids - therapeutic use
- Immunoblotting - methods
- Microscopy, Electron -
- Protein Kinases - metabolism
- Sarcoma, Endometrial Stromal - drug therapy
- Sarcoma, Endometrial Stromal - pathology
- TOR Serine-Threonine Kinases -
- Vorinostat -
- Find related publications in this database (Keywords)
- uterus
- endometrial stromal sarcoma
- histone deacetylase
- SAHA
- G1 arrest
- autophagy
- mTOR