Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession

Liu, Yuanrong; Song, Dandan; Liang, Dongmin; Li, Youjie; Yan, Yun‐Fei; Sun, Hanyong; Zhang, Meiling; Hu, Jinxia; Zhao, Yu-Long; Liang, Yan; Li, Yanmei; Yang, Zhen; Wang, Ranran; Zheng, Hou-Feng; Wang, Pingyu; Xie, Songqiang

doi:10.1038/s41420-022-01095-1

Cited by 12 publications

(11 citation statements)

References 46 publications

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“…Furthermore, we found knockdown of TRIB2 to significantly inhibit PDGF‐BB‐induced VSMC proliferation, indicating that PDGF‐BB‐induced TRIB2 expression positively regulates VSMC proliferation. Our findings are consistent with previous reports that TRIB2 knockdown impairs the growth ability of various cancer cells, including HepG2 cells and HCT116 cells (a human colon cancer cell line) (Liu et al, 2022). However, another study did not detect any significant effects of TRIB2 silencing on the proliferation of HL7702 hepatocytes (Wang et al, 2013).…”

Section: Discussionsupporting

confidence: 94%

“…Thus, increased TRIB2 expression may significantly affect VSMC proliferation and influence neointima formation. Our data supports previous studies that have reported TRIB2 overexpression in the proliferative stage of cancers such as lung and liver cancer (Liu et al, 2022). Accordingly, TRIB2 may play an important role in the initiation of cell proliferation.…”

Section: Discussionsupporting

confidence: 93%

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The role of tribbles homolog 2 in vascular smooth muscle cell proliferation

Takaguri

Ishizaka

Maki

et al. 2023

Cell Biology International

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Tribbles homolog 2 (TRIB2) functions as an adapter protein that regulates signal transductions involved in a variety of cellular functions, including tumorigenesis. However, the role of TRIB2 in the proliferation of vascular smooth muscle cells (VSMCs) and the underlying expression mechanisms remain unclear. The present study investigated the role of TRIB2 in VSMC proliferation and revealed that TRIB2 expression increases following vascular injury and platelet‐derived growth factor (PDGF)‐BB‐stimulated VSMCs. We found that pretreatment with diphenyleneiodonium (a nicotinamide adenine dinucleotide phosphate oxidase inhibitor), U0126 (an inhibitor of mitogen‐activated protein kinase kinase 1 [MEK1]), or siRNA targeting the gene encoding early growth response 1 (EGR‐1) significantly inhibits PDGF‐BB‐induced TRIB2 expression in VSMCs. Furthermore, TRIB2 knockdown significantly inhibits PDGF‐BB‐induced proliferation of VSMCs but does not affect the phosphorylation of AKT. However, phosphorylation of ERK1 and expression of proliferating cell nuclear antibody are significantly suppressed in VSMCs by PDGF‐BB stimulation. Thus, PDGF‐BB‐induced TRIB2 expression is mediated by ROS/ERK/EGR‐1 pathways and plays a critical role in VSMC proliferation via modulation of ERK activity. We propose TRIB2 as a promising therapeutic target for the prevention of neointima formation and vascular disease.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 93%

The role of tribbles homolog 2 in vascular smooth muscle cell proliferation

Takaguri

Ishizaka

Maki

et al. 2023

Cell Biology International

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“…Glucose carbons are essential for biomass synthesis through the glycolysis and the pentose phosphate pathways, with lactic acid and nucleic acid precursors produced as major end products ( 14 , 70 , 71 ). The pyruvate kinase M2 (PKM2) isoform, which is abundantly expressed in most malignant cancers, produces pyruvate-derived lactic acid with minimal ATP synthesis ( 14 , 72 – 75 ). In other words, most of the glucose-derived lactic acid coming from the tumor cells is produced with little ATP synthesis through glycolysis.…”

Section: Fermentation Metabolites Acidify the Gbm Microenvironmentmentioning

confidence: 99%

“…The glutaminolysis pathway (red) becomes dominant in tumor cells with inefficient OxPhos and that express the dimeric PKM2 isoform. PKM2 is expressed in GBM and produces less ATP through glycolysis than does the PKM1 isoform ( 73 , 75 , 195 , 196 ). The elevation of ketone bodies (D-β-hydroxybutyrate and acetoacetate) through KD will indirectly reduce ATP synthesis through the succinate CoA ligase (SUCL) reaction by diverting CoA from succinate to acetoacetate.…”

Section: The Simultaneous Restriction Of Glutamine and Glucose Will R...mentioning

confidence: 99%

Metabolic management of microenvironment acidity in glioblastoma

et al. 2022

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Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.

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“…These findings are consistent with previous studies showing that PKM2 isoform is expressed in various human glioma cell lines (Luan et al, 2015). Unlike the PKM1 isoform, which produces ATP in the glycolytic pathway, the dimerized PKM2 isoform exists as a low-affinity enzyme which diverts phosphoenolpyruvate toward auxiliary pathways that result in lactate production while circumventing the net ATP step in glycolysis (Liu and Vander Heiden, 2015; Chinopoulos, 2020; Seyfried et al, 2020; Liu et al, 2022). Hence, caution is necessary in considering lactate as a quantitative biomarker for ATP content through glycolysis in glioma cells that express the PKM2 isoform.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells

Lee,

Ta,

Mukherjee

et al. 2024

Preprint

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Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: 1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; 2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; 3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.

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Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession

Cited by 12 publications

References 46 publications

The role of tribbles homolog 2 in vascular smooth muscle cell proliferation

The role of tribbles homolog 2 in vascular smooth muscle cell proliferation

Metabolic management of microenvironment acidity in glioblastoma

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells

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