Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China; Key Laboratory of Pharmaceutical Research for Metabolic Diseases, Qingdao University of Science and Technology, China.
Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology, Qingdao, Shandong, 266035, China.
Food Chem Toxicol. 2020 Mar;137:111158. doi: 10.1016/j.fct.2020.111158. Epub 2020 Jan 25.
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.
eIF4E/eIF4G 复合物在翻译起始阶段的基因表达调控中发挥核心作用。本研究旨在确定新型小分子化合物 TPDHT 是否可以破坏 eIF4E/eIF4G 的相互作用，并且是否可以在体内表现出优异的抗肿瘤活性而没有明显的毒性作用。本研究在体外和体内研究了 TPDHT 的抗肿瘤机制。TPDHT 对人肺癌 A549 细胞表现出显著的增殖抑制活性，并诱导 G0/G1 期细胞周期阻滞。此外，TPDHT 还通过线粒体介导的凋亡途径诱导 A549 细胞凋亡。我们的结果表明，TPDHT 可以破坏 eIF4E/eIF4G 的相互作用，并且 eIF4F 的活性在 TPDHT 诱导的细胞增殖抑制和凋亡中起重要作用。进一步的研究表明，TPDHT 可以抑制 Ras/ERK/MNK 通路，ERK 通路的激活逆转了 TPDHT 诱导的细胞增殖抑制和凋亡。总之，我们的研究结果表明，TPDHT 通过 ERK/MNK/eIF4F 通路控制的内在凋亡途径发挥抗肿瘤作用。
