The cap-translation inhibitor 4EGI-1 induces mitochondrial dysfunction via regulation of mitochondrial dynamic proteins in human glioma U251 cells

Yang, Xin; Dong, Qingshan; Liu, Liwen; Huo, Jianhua; Li, Peng-Qi; Zhou, Fei; Zhen, Hai‐Ning

doi:10.1016/j.neuint.2015.07.019

Cited by 11 publications

(11 citation statements)

References 40 publications

(35 reference statements)

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“…Interestingly, mitochondrial dynamics act as critical cell cycle control mechanisms with highly-motile organelles arranging themselves to ensure mitochondrial homogenization and segregation during cell division (Antico Arciuch et al, 2012; Mishra and Chan, 2014). Mitochondrial fusion is required for maintaining mitochondrial membrane potential and for permitting entry into S-phase, meanwhile mitochondrial fission is required at later stages, notably to impart a mitochondrial population to each daughter cell during cytokinesis (Taguchi et al, 2007; Schieke et al, 2008; Yang et al, 2015). Although specific mechanisms linking mitochondrial fusion and fission factors to cell cycle regulatory proteins have not been characterized in glioma cells, mitochondrial dynamics do appear to be tightly tied to cell cycle progression, providing a potentially critical process linking cellular bio-energetics with growth.…”

Section: Autophagy: You Are What You Eatmentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

266

269

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Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

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Section: Autophagy: You Are What You Eatmentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

266

269

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“…In our previous studies, U251 cells were treated with the eIF4E inhibitor 4EGI-1, and its suppressive effect on cell growth was observed (28). It has been confirmed that the initiation of the translation of cyclin D1 and C-myc are dependent on the eIF4F complex, which directly promotes the proliferation of cancer cells (4).…”

Section: Discussionmentioning

confidence: 73%

Inhibition of eIF4F complex loading inhibits the survival of malignant glioma

Dong

Yan

et al. 2018

Oncol Rep

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The eukaryotic initiation factor (eIF)4E‑binding proteins (4E‑BPs) regulate cap‑dependent protein translation and control the assembly of the eIF4F complex. In the present study, a phosphorylation‑deficient truncated 4E‑BP2 (eIF4FD) was constructed into the eukaryotic expression vector pSecTag2, and the in vitro and in vivo effects on malignant glioma survival were determined through inhibiting eIF4F complex assembly. Cell cycle distribution analysis and TUNEL staining show that overexpression of eIF4FD suppressed cell proliferation and induced apoptosis in U251 cells. Western blotting showed that the cell cycle‑related genes cyclin D1 and C‑myc, and anti‑apoptotic genes B‑cell lymphoma 2 (Bcl‑2), Bcl‑extra large and survivin were reduced following the overexpression of eIF4FD. Furthermore, eIF4FD suppressed glioma vascularization via reductions in the expression of β‑catenin and vascular endothelial growth factor. In the orthotopic xenograft model, the stable expression of eIF4FD in U251 cells attenuated cell growth and increased the rate of apoptosis. Accordingly, pSecTag2‑PTD‑eIF4FD injection via the tail vein of mice also lead to cell growth inhibition and the induction of apoptosis. Therefore, the study showed that phosphorylation‑deficient truncated 4E‑BP2 efficiently inhibited eIF4E and prevented the formation of the eIF4F complex, which further contributed to the inhibition of cell proliferation and vascularization, and the induction of apoptosis. Therefore, the 4E‑BP2‑based phosphorylation‑deficient truncation designed in the present study may represent a novel approach for the targeted therapy of human malignant glioma though inhibition of the translation initiation complex.

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“…For example, the anticancer drug 4EGI-1 causes apoptosis and mitochondria fragmentation in glioma cells and, in agreement, the cells had decreased levels of Mfn-1 and Opa1 and increased levels of Drp1. 49 In addition, blocking mitochondrial fragmentation by Drp1-siRNA prevented the antitumor effects of 4EGI-1. 49 Moreover, small human heat-shock protein (HSPB11), which has been associated with brain tumor malignancy, inhibits cell death possibly through enhancing the inhibitory phosphorylation of Drp1, which leads to decreased apoptosis.…”

Section: Apoptosismentioning

confidence: 99%

“…49 In addition, blocking mitochondrial fragmentation by Drp1-siRNA prevented the antitumor effects of 4EGI-1. 49 Moreover, small human heat-shock protein (HSPB11), which has been associated with brain tumor malignancy, inhibits cell death possibly through enhancing the inhibitory phosphorylation of Drp1, which leads to decreased apoptosis. 50 Consistent with this, others have found that the kinase inhibitor tyrphostin A9 induces cancer cell death by Drp1-mediated mitochondrial fragmentation.…”

Section: Apoptosismentioning

confidence: 99%

Dynamins and BAR Proteins-Safeguards against Cancer

Sundborger

Hinshaw

2015

Crit Rev Oncog

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Dynamins and BAR proteins are crucial in a wide variety of cellular processes for their ability to mediate membrane remodeling, such as membrane curvature and membrane fission and fusion. In this review, we highlight dynamins and BAR proteins and the cellular mechanisms that are involved in the initiation and progression of cancer. We specifically discuss the roles of these proteins in endocytosis, endo-lysosomal trafficking, autophagy, and apoptosis as these processes are all tightly linked to membrane remodeling and cancer.

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The cap-translation inhibitor 4EGI-1 induces mitochondrial dysfunction via regulation of mitochondrial dynamic proteins in human glioma U251 cells

Cited by 11 publications

References 40 publications

Metabolic Reprogramming in Glioma

Metabolic Reprogramming in Glioma

Inhibition of eIF4F complex loading inhibits the survival of malignant glioma

Dynamins and BAR Proteins-Safeguards against Cancer

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