The synthetic chalcone derivative 2-hydroxy-3',5,5'-trimethoxychalcone induces unfolded protein response-mediated...

The synthetic chalcone derivative 2-hydroxy-3',5,5'-trimenthoxyochalcone (named DK-139) exhibits anti-inflammatory and anti-tumor invasion properties. However, effects of DK-139 on tumor cell growth remain unknown. In the present study, we evaluated the inhibitory activity of DK-139 against human lung cancer cells. Treatment with DK-139 inhibited clonogenicity in various lung cancers and stimulated the caspase cascade, leading to the apoptosis of A549 lung cancer cells. To investigate the mode of action of DK-139-induced apoptosis, we analyzed the effect of DK-139 on the endoplasmic reticulum (ER) stress response. DK-139 increased expression of ER stress sensors, including p-PERK, GRP78/BiP, and IRE1α. IRE1α-regulated XBP-1 mRNA splicing and PERK-induced ATF4 expression was also upregulated following DK-139 treatment. In addition, expression levels of the pro-apoptotic transcription factor CHOP and its downstream target Bim, which is involved in mitochondria-mediated apoptosis, were increased by DK-139 treatment. These results suggest that DK-139 triggers caspase-mediated apoptosis via the ER stress-activated unfolded protein response (UPR) pathway. We propose that the synthetic chalcone derivative DK-139 may be used as a potential agent for the prevention and/or treatment of human lung cancer.