title: The Histone Deacetylase Inhibitor Trichostatin A Sensitizes Human Renal Carcinoma Cells to TRAIL-Induced Apoptosis through Down-Regulation of c-FLIPL.
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.
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-851.
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Han
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Dongeui University, Busan 614-714.
authors.forename: Cheol
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701.
authors.forename: Taek Kyu
authors.initials: TK
authors.lastname: Kwon
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Department of Urology, College of Medicine, Chungbuk National University, Cheongju 362-763.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Oriental Medicine, Dong-Eui University, Busan 614-851.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-851 ; Anti-Aging Research Center & Blue-BioIndustry RIC, Dongeui University, Busan 614-714, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
keywords: Apoptosis; TRAIL; Trichostatin A; c-FLIPL