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Histone deacetylase inhibitors cooperate with IFN-γ to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8.
- Source :
- Oncogene; 9/3/2009, Vol. 28 Issue 35, p3097-3110, 14p, 6 Graphs
- Publication Year :
- 2009
-
Abstract
- Evasion of apoptosis can be caused by epigenetic silencing of caspase-8, a key component of the extrinsic apoptosis pathway. Loss of caspase-8 correlates with poor prognosis in medulloblastoma, which highlights the relevance of strategies to upregulate caspase-8 to break apoptosis resistance. Here, we develop a new combinatorial approach, that is treatment using histone deacetylase inhibitors (HDACI) together with interferon (IFN)-γ, to restore caspase-8 expression and to overcome resistance to the death-receptor ligand TNF-related apoptosis-inducing ligand (TRAIL) in medulloblastoma in vitro and in vivo. HDACI, for example, valproic acid (VA), suberoylanilide hydroxamic acid (SAHA) and MS-275, cooperate with IFN-γ to upregulate caspase-8 in cancer cells lacking caspase-8, thereby restoring sensitivity to TRAIL-induced apoptosis. Molecular studies show that VA promotes histone acetylation and acts in concert with IFN-γ to stimulate caspase-8 promoter activity. The resulting increase in caspase-8 mRNA and protein expression leads to enhanced TRAIL-induced activation of caspase-8 at the death-inducing signaling complex, mitochondrial outer-membrane permeabilization and caspase-dependent cell death. Intriguingly, pharmacological or genetic inhibition of caspase-8 also abolishes the VA/IFN-γ-mediated sensitization for TRAIL-induced apoptosis. It is important to note that VA and IFN-γ restore caspase-8 expression and sensitivity to TRAIL in primary medulloblastoma samples and significantly potentiate TRAIL-mediated suppression of medulloblastoma growth in vivo. These findings provide the rationale for further (pre)clinical evaluation of VA and IFN-γ to restore caspase-8 expression and apoptosis sensitivity in cancers with caspase-8 silencing and open new perspectives to overcome TRAIL resistance. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09509232
- Volume :
- 28
- Issue :
- 35
- Database :
- Complementary Index
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 44012493
- Full Text :
- https://doi.org/10.1038/onc.2009.161