title: The cap-translation inhibitor 4EGI-1 induces mitochondrial dysfunction via regulation of mitochondrial dynamic proteins in human glioma U251 cells.
abstract: Translation initiation factors (eIFs) are over-activated in many human cancers and may contribute to their progression. The small molecule 4EGI-1, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anti-cancer effects in human cancer cells. The goal of the present study was to evaluate the anti-cancer effects of 4EGI-1 in human glioma U251 cells. We found that 4EGI-1 impaired the assembly of the eIF4F complex, and inhibited proliferation of U251 cells via inducing apoptosis. 4EGI-1 treatment induced collapse of mitochondrial membrane potential (MMP) and production of intracellular reactive oxygen species (ROS), which were prevented by the ROS scavenger N-acetyl-cysteine (NAC). In addition, 4EGI-1 inhibited mitochondrial ATP synthesis via suppressing complex I activity, but had no effects on mitochondrial biogenesis. The results of fluorescence staining showed that 4EGI-1 indeed fragmented the mitochondrial network of U251 cells. We found a significant decrease in optic atrophy type 1 (Opa-1) and mitofusin 1 (Mfn-1) related to fusion proteins as well as an increase in fission protein dynamin-related protein 1 (Drp-1). Furthermore, the anti-cancer effects of 4GI-1 were partially nullified by knock down of Drp-1 using siRNA. These data indicate that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for human glioma therapy.
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi 710032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi 710032, China.
authors.forename: Qiu-Feng
authors.initials: QF
authors.lastname: Dong
authors.affiliation: Department of Bioscience, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, Shaanxi 710069, China.
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi 710032, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Huo
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi 710032, China.
authors.forename: Peng-Qi
authors.initials: PQ
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi 710032, China. Electronic address: fmmuzhoufei@163.com.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fei
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi 710032, China. Electronic address: fmmuzhenhaining@126.com.
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Zhen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C517852:4EGI-1 compound; D006835:Hydrazones; D011500:Protein Synthesis Inhibitors; D013844:Thiazoles
keywords: 4EGI-1; Fission; Fusion; Glioma; Mitochondrial biogenesis; U251 cells