Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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The Histone Deacetylase Inhibitor Trichostatin A Sensitizes Human Renal Carcinoma Cells to TRAIL-Induced Apoptosis through Down-Regulation of c-FLIPL

  • Han, Min Ho (Department of Biochemistry, College of Oriental Medicine, Dong-Eui University) ;
  • Park, Cheol (Department of Molecular Biology, College of Natural Sciences, Dongeui University) ;
  • Kwon, Taek Kyu (Department of Immunology, School of Medicine, Keimyung University) ;
  • Kim, Gi-Young (Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University) ;
  • Kim, Wun-Jae (Department of Urology, College of Medicine, Chungbuk National University) ;
  • Hong, Sang Hoon (Department of Internal Medicine, College of Oriental Medicine, Dong-Eui University) ;
  • Yoo, Young Hyun (Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center) ;
  • Choi, Yung Hyun (Department of Biochemistry, College of Oriental Medicine, Dong-Eui University)
  • Received : 2014.08.11
  • Accepted : 2014.10.07
  • Published : 2015.01.01
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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-$1{\beta}$-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-$FLIP_L$-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

References

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