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.
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Authors | R G P T Jayasooriya, Dong-Oh Moon, Sung Gyu Yun, Yung Hyun Choi, Yukihiro Asami, Mun-Ock Kim, Jae-Hyuk Jang, Bo Yeon Kim, Jong Seog Ahn, Gi-Young Kim |
Journal | Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
(Food Chem Toxicol)
Vol. 55
Pg. 1-7
(May 2013)
ISSN: 1873-6351 [Electronic] England |
PMID | 23306790
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Elsevier Ltd. All rights reserved. |
Chemical References |
- Eukaryotic Initiation Factor-2
- NF-kappa B
- TNF-Related Apoptosis-Inducing Ligand
- TNFSF10 protein, human
- Trichothecenes
- fas Receptor
- muconomycin A
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Topics |
- Animals
- Apoptosis
(drug effects, physiology)
- Blotting, Western
- Cell Survival
(drug effects)
- Eukaryotic Initiation Factor-2
(physiology)
- Hep G2 Cells
- Humans
- Mice
- NF-kappa B
(physiology)
- Spleen
(cytology, drug effects, metabolism)
- TNF-Related Apoptosis-Inducing Ligand
(physiology)
- Trichothecenes
(pharmacology)
- fas Receptor
(metabolism)
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