Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP
| Autor: | I Eckhardt, J Lausen, Simone Fulda, Sri HariKrishna Vellanki, S Cristofanon, Häcker S, Behnaz Ahangarian Abhari, S Kolodziej, A Bangert, K-M Debatin |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Cell Membrane Permeability CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Biology Molecular oncology Proto-Oncogene Proteins c-myc TNF-Related Apoptosis-Inducing Ligand Growth factor receptor Downregulation and upregulation Cell Line Tumor Genetics Humans Molecular Biology Cell Proliferation Receptors Death Domain Cell cycle NFKB1 Molecular biology nervous system diseases Enzyme Activation Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors Caspases Mitochondrial Membranes Cancer cell Cancer research Histone deacetylase Glioblastoma |
| Zdroj: | Oncogene. 31:4677-4688 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2011.614 |
| Popis: | Glioblastoma is the most common primary brain tumor with a very poor prognosis, calling for novel treatment strategies. Here, we provide first evidence that histone deacetylase inhibitors (HDACI) prime glioblastoma cells for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis at least in part by c-myc-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP). Pretreatment with distinct HDACI (MS275, suberoylanilide hydroxamic acid, valproic acid) significantly enhances TRAIL-induced apoptosis in several glioblastoma cell lines. Monitoring a panel of apoptosis-regulatory proteins revealed that MS275 reduces the expression of cFLIP(L) and cFLIP(S). This leads to decreased recruitment of cFLIP(L) and cFLIP(S) and increased activation of caspase-8 to the TRAIL death-inducing signaling complex, resulting in enhanced cleavage of caspase-8, -9 and -3 and caspase-dependent apoptosis. Also, MS275 promotes TRAIL-triggered processing of Bid, activation of Bax, loss of mitochondrial membrane potential and release of cytochrome c. MS275-mediated downregulation of cFLIP occurs at the mRNA level independent of proteasome- or caspase-mediated degradation, and is preceded by upregulation of nuclear levels of c-myc, a transcriptional repressor of cFLIP. Notably, MS275 causes increased binding of c-myc to the cFLIP promoter and reduces cFLIP promoter activity. Indeed, knockdown of c-myc partially rescues cFLIP(L) from MS275-inferred downregulation and significantly decreases TRAIL- and MS275-induced apoptosis. Also, overexpression of cFLIP(L) or cFLIP(S) significantly reduces MS275- and TRAIL-induced apoptosis. Importantly, MS275 sensitizes primary cultured glioblastoma cells towards TRAIL and cooperates with TRAIL to reduce long-term clonogenic survival of glioblastoma cells and to suppress glioblastoma growth in vivo underscoring the clinical relevance of this approach. Thus, these findings demonstrate that HDACI represent a promising strategy to prime glioblastoma for TRAIL-induced apoptosis by targeting cFLIP. |
| Databáze: | OpenAIRE |
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