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The Histone Deacetylase Inhibitor Trichostatin A Sensitizes Human Renal Carcinoma Cells to TRAIL-Induced Apoptosis through Down-egulation of c-FLIP

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Author(s)
Min Ho HanCheol ParkTaek Kyu KwonGi-Young KimWun-Jae KimSang Hoon HongYoung Hyun YooYung Hyun Choi
Keimyung Author(s)
Kwon, Taeg Kyu
Department
Dept. of Immunology (면역학)
Journal Title
Biomolecules & Therapeutics.
Issued Date
2015
Volume
23
Issue
1
Abstract
Histone acetylation plays a critical role in the regulation of transcription by altering the structure of chromatin, and it may influence the resistance of some tumor cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) by regulating the gene expression of components of the TRAIL signaling pathway. In this study, we investigated the effects and molecular mechanisms of trichostatin A (TSA), a histone deacetylase inhibitor, in sensitizing TRAIL-induced apoptosis in Caki human renal carcinoma cells. Our results indicate that nontoxic concentrations of TSA substantially enhance TRAIL-induced apoptosis compared with treatment with either agent alone. Cotreatment with TSA and TRAIL effectively induced cleavage of Bid and loss of mitochondrial membrane potential (MMP), which was associated with the activation of caspases (-3, -8, and -9) and degradation of poly (ADP-ribose) polymerase (PARP), contributing toward the sensitization to TRAIL. Combined treatment with TSA and TRAIL significantly reduced the levels of the cellular Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme (FLICE) inhibitory protein (c-FLIP), whereas those of death receptor (DR) 4, DR5, and FADD remained unchanged. The synergistic effect of TAS and TRAIL was perfectly attenuated in c-FLIPL-overexpressing Caki cells. Taken together, the present study demonstrates that down-regulation of c-FLIP contributes to TSA-facilitated TRAIL-induced apoptosis, amplifying the death receptor, as well as mitochondria-mediated apoptotic signaling pathways.


KEYWORDS:

Apoptosis; TRAIL; Trichostatin A; c-FLIPL
Keimyung Author(s)(Kor)
권택규
Publisher
School of Medicine
Citation
Min Ho Han et al. (2015). The Histone Deacetylase Inhibitor Trichostatin A Sensitizes Human Renal Carcinoma Cells to TRAIL-Induced Apoptosis through Down-egulation of c-FLIP. Biomolecules & Therapeutics., 23(1), 31–38. doi: 10.4062/biomolther.2014.092
Type
Article
ISSN
1976-9148
DOI
10.4062/biomolther.2014.092
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35218
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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