The ERK-MNK-eIF4F signaling pathway mediates TPDHT-induced A549 cell death in vitro and in vivo. (March 2020)

• Record Type: Journal Article
• Authors: Guo, Chuanlong; Hou, Yuzhen; Yu, Xuemin; Zhang, Fan; Wu, Xiaochen; Wu, Xianggen; Wang, Lijun
• Is Part Of: Food and chemical toxicology. Volume 137(2020)
• Publication Date: 2020-03
• Subjects: Apoptosis -- eIF4F -- ERK -- MNK -- A549 cells; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2020.111158
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: The eIF4E/eIF4G complex plays a central role in gene expression regulation during the initial stage of translation. This study aimed to determine if the novel small molecule compound, TPDHT, could disrupt the interaction of eIF4E/eIF4G, and if it could exhibit excellent antitumor activity in vivo without causing apparent toxicity effect. This study investigated the antitumor mechanism of TPDHT in vitro and in vivo . TPDHT showed significant anti-proliferative activity on human lung cancer A549 cells, and it induced G0/G1 cycle arrest. Moreover, TPDHT also induced A549 cell apoptosis through the mitochondria-mediated apoptotic pathway. Our results indicate that TPDHT could disrupt the interaction of eIF4E/eIF4G, and the activity of eIF4F plays an important role in TPDHT-induced cell proliferation inhibition and apoptosis. Further research showed that TPDHT could inhibit the Ras/ERK/MNK pathway, and activation of the ERK pathway reversed TPDHT-induced cell proliferation inhibition and apoptosis. Taken together, our study findings indicated that TPDHT exerts an antitumor effect through an intrinsic apoptotic pathway controlled by the ERK/MNK/eIF4F pathway. Graphical abstract: Image 1 Highlights: TPDHT disrupts eIF4E/eIF4G interaction. TPDHT exhibits anticancer activity in vitro and in vivo . TPDHT induces apoptosis and cell cycle arrest by targeting ERK/MNK/eIF4F.