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Induction of Human-Lung-Cancer-A549-Cell Apoptosis by 4-Hydroperoxy-2-decenoic Acid Ethyl Ester through Intracellular ROS Accumulation and the Induction of Proapoptotic CHOP Expression

Kamiya, Tetsuro, Watanabe, Momoko, Hara, Hirokazu, Mitsugi, Yukari, Yamaguchi, Eiji, Itoh, Akichika, Adachi, Tetsuo
Journal of agricultural and food chemistry 2018 v.66 no.41 pp. 10741-10747
DNA fragmentation, acetylcysteine, anticarcinogenic activity, antioxidant activity, apoptosis, endoplasmic reticulum stress, fatty acids, honey bees, mitogen-activated protein kinase, neoplasm cells, reactive oxygen species, royal jelly
Royal jelly, a natural product secreted by honeybees, contains several fatty acids, such as 10-hydroxy-2-decenoic acid (DE), and shows anti- and pro-apoptotic properties. 4-Hydroperoxy-2-decenoic acid ethyl ester (HPO-DAEE), a DE derivative, exhibits potent antioxidative activity; however, it currently remains unclear whether HPO-DAEE induces cancer-cell death. In the present study, treatment with HPO-DAEE induced human-lung-cancer-A549-cell death (52.7 ± 10.2%) that was accompanied by DNA fragmentation. Moreover, the accumulation of intracellular reactive oxygen species (ROS, 2.38 ± 0.1-fold) and the induction of proapoptotic CCAAT-enhancer-binding-protein-homologous-protein (CHOP) expression (18.4 ± 4.0-fold) were observed in HPO-DAEE-treated cells. HPO-DAEE-elicited CHOP expression and cell death were markedly suppressed by pretreatment with N-acetylcysteine (NAC), an antioxidant, by 2.40 ± 1.57-fold and 5.7 ± 1.6%, respectively. Pretreatment with 4-phenylbutyric acid (PBA), an inhibitor of endoplasmic reticulum stress, also suppressed A549-cell death (38.4 ± 1.1%). Furthermore, we demonstrated the involvement of extracellular-signal-regulated protein kinase (ERK) and p38-related signaling in HPO-DAEE-elicited cell-death events. Overall, we concluded that HPO-DAEE induces A549-cell apoptosis through the ROS–ERK–p38 pathway and, at least in part, the CHOP pathway.