title: Verrucarin A enhances TRAIL-induced apoptosis via NF-κB-mediated Fas overexpression.
abstract: We investigated whether verrucarin A (VA) sensitizes HepG2 hepatoma cells to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. We found that VA alone induces little apoptosis, but when combined with TRAIL (VA/TRAIL), it triggered significant apoptosis, causing little or no toxicity in normal mouse splenocytes. VA/TRAIL-induced cell death is involved in the loss of mitochondrial transmembrane potential and the consequent activation of caspases. Because nuclear factor (NF)-κB inhibition has been known as a critical target in TRAIL-mediated apoptosis, we also investigated the role of NF-κB in VA/TRAIL treatment. We found that VA upregulated the DNA binding activity of NF-κB, but that the antioxidants glutathione and N-acetyl-l-cysteine, as well as NF-κB inhibitor MG132, and mutant-IκB (m-IκB) transfection, significantly downregulated VA/TRAIL-induced cell death by inhibiting caspase-3 and NF-κB activities. Transfection of mutant-eIF2α also resulted in a decrease in VA/TRAIL-induced cell death by inhibiting of caspase-3, but not NF-κB activity. Although VA/TRAIL treatment led to an increase of DR5 expression, transfection of m-IκB had no influence on the DR5 expressional level. Finally, we showed that NF-κB-mediated Fas expression is critical to VA/TRAIL-induced apoptosis. Taken together, these results indicate that VA/TRAIL sensitizes HepG2 cells to apoptosis via NF-κB-mediated overexpression of Fas.
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: R G P T
authors.initials: RG
authors.lastname: Jayasooriya
authors.forename: Dong-Oh
authors.initials: DO
authors.lastname: Moon
authors.forename: Sung Gyu
authors.initials: SG
authors.lastname: Yun
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Asami
authors.forename: Mun-Ock
authors.initials: MO
authors.lastname: Kim
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Jang
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.forename: Jong Seog
authors.initials: JS
authors.lastname: Ahn
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D014255:Trichothecenes / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014255:Trichothecenes; D019014:fas Receptor; C005348:muconomycin A