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A novel synthetic chalcone derivative promotes caspase-dependent apoptosis through ROS generation and activation of the UPR in MH7A cells

Author:
Kim, Jin-Hyun, Jeon, Yong-Joon, Cho, Jaewook, Shin, Jong-Il, Baek, Chae Yun, Lim, Yoongho, Koh, Dongsoo, Shin, Soon Young, Lee, Young Han, Lee, Kyungho
Source:
Genes & genomics 2015 v.37 no.12 pp. 1051-1059
ISSN:
1976-9571
Subject:
NAD ADP-ribosyltransferase, acetylcysteine, antioxidants, apoptosis, binding proteins, biosynthesis, caspase-3, caspase-7, cell viability, chalcone, gene expression regulation, genes, polyphenols, reactive oxygen species, rheumatoid arthritis, secondary metabolites, unfolded protein response
Abstract:
Chalcones, one class of polyphenolic compounds synthesized as secondary metabolites during flavonoid biosynthesis in plants, have anti-inflammatory and antitumorigenic effects. In this study, we investigated the roles of a novel chalcone derivative, (E)-3-(3,5-dimethoxyphenyl)-1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one (DK-59), on rheumatoid arthritis (RA) fibroblast-like synoviocyte MH7A cells. DK-59 treatment reduced cell viability and induced caspase-mediated apoptosis in MH7A cells; activation of caspase-7 and caspase-3, as well as fragmentation of poly (ADP-ribose) polymerase (PARP-1), occurred in a time-dependent manner, and treatment with a pan-caspase inhibitor, Z-VAD, significantly reduced DK-59-mediated PARP-1 cleavage. DK-59-mediated apoptosis was caused by the production of intracellular reactive oxygen species (ROS); DK-59 treatment induced ROS production in a time-dependent manner, and treatment with the antioxidant N-acetyl-L-cysteine significantly inhibited DK-59-mediated fragmentation of PARP-1 and recovered cell viability. Many genes that function in the unfolded protein response (UPR), including inositol-requiring protein 1, X-box binding protein 1, and C/EBP homologous protein (CHOP), were upregulated by DK-59 treatment. CHOP knockdown by lentivirus infection reduced DK-59-mediated PARP-1 cleavage, suggesting that CHOP plays a proapoptotic role in DK-59-mediated apoptosis in MH7A cells. Taken together, the results suggest that DK-59-mediated induction of ROS and activation of the UPR can be used as a target for the therapeutic treatment of RA.
Agid:
4666164