Main content area

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

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
Genes & genomics 2015 v.37 no.12 pp. 1051-1059
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
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.