Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Niu, Nan; Ye, Jinfeng; Hu, Zhangli; Zhang, Junbin; Wang, Yun

doi:10.3390/ijms24087076

Cited by 6 publications

(2 citation statements)

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“…The upregulation of these genes in GBM tissues, and additionally in brain CSC models, further suggests their association with stemness properties and invasive characteristics. Whether G6PC3 and SLC37A4 may contribute, in part through G6P sensing processes, to the pro-angiogenic phenotype of GBM remains speculative, but would align with previous studies indicating the involvement of glucose metabolism alterations in angiogenesis regulation ( 63 , 64 ). Targeting components of the G6Pase system, either involved in the G6P recognition/transport or hydrolysis within the ER, may potentially provide a novel approach to modulate angiogenesis in GBM.…”

Section: Discussionsupporting

confidence: 81%

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype

Torabidastgerdooei,

Roy,

Annabi

2023

Front. Endocrinol.

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BackgroundGlycogen plays an important role in glucose homeostasis and contributes to key functions related to brain cancer cell survival in glioblastoma multiforme (GBM) disease progression. Such adaptive molecular mechanism is dependent on the glycogenolytic pathway and intracellular glucose-6-phosphate (G6P) sensing by brain cancer cells residing within those highly hypoxic tumors. The involvement of components of the glucose-6-phosphatase (G6Pase) system remains however elusive.ObjectiveWe questioned the gene expression levels of components of the G6Pase system in GBM tissues and their functional impact in the control of the invasive and brain cancer stem cells (CSC) phenotypes.MethodsIn silico analysis of transcript levels in GBM tumor tissues was done by GEPIA. Total RNA was extracted and gene expression of G6PC1-3 as well as of SLC37A1-4 members analyzed by qPCR in four human brain cancer cell lines and from clinically annotated brain tumor cDNA arrays. Transient siRNA-mediated gene silencing was used to assess the impact of TGF-β-induced epithelial-to-mesenchymal transition (EMT) and cell chemotaxis. Three-dimensional (3D) neurosphere cultures were generated to recapitulate the brain CSC phenotype.ResultsHigher expression in G6PC3, SLC37A2, and SLC37A4 was found in GBM tumor tissues in comparison to low-grade glioma and healthy tissue. The expression of these genes was also found elevated in established human U87, U251, U118, and U138 GBM cell models compared to human HepG2 hepatoma cells. SLC37A4/G6PC3, but not SLC37A2, levels were induced in 3D CD133/SOX2-positive U87 neurospheres when compared to 2D monolayers. Silencing of SLC37A4/G6PC3 altered TGF-β-induced EMT biomarker SNAIL and cell chemotaxis.ConclusionTwo members of the G6Pase system, G6PC3 and SLC37A4, associate with GBM disease progression and regulate the metabolic reprogramming of an invasive and CSC phenotype. Such molecular signature may support their role in cancer cell survival and chemoresistance and become future therapeutic targets.

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Section: Discussionsupporting

confidence: 81%

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype

Torabidastgerdooei,

Roy,

Annabi

2023

Front. Endocrinol.

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“…Maintenance of this state is mediated primarily by two molecules: sphingosine 1-phosphate (S1P) and interleukin (IL)-7 ( Goronzy et al, 2015 ; Mendoza et al, 2017 ). S1P is important for OXPHOS ( Mendoza et al, 2017 ), while IL-7 mainly promotes glucose uptake by GLUT-1, affecting the glycolysis process ( Niu et al, 2023 ). Glycolysis is primarily used to activate T cells, but OXPHOS are also important, and their absence prevents T cell proliferation ( Tarasenko et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Natural products target glycolysis in liver disease

Li,

Hao,

2023

Front. Pharmacol.

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Mitochondrial dysfunction plays an important role in the occurrence and development of different liver diseases. Oxidative phosphorylation (OXPHOS) dysfunction and production of reactive oxygen species are closely related to mitochondrial dysfunction, forcing glycolysis to become the main source of energy metabolism of liver cells. Moreover, glycolysis is also enhanced to varying degrees in different liver diseases, especially in liver cancer. Therefore, targeting the glycolytic signaling pathway provides a new strategy for the treatment of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis associated with liver cancer. Natural products regulate many steps of glycolysis, and targeting glycolysis with natural products is a promising cancer treatment. In this review, we have mainly illustrated the relationship between glycolysis and liver disease, natural products can work by targeting key enzymes in glycolysis and their associated proteins, so understanding how natural products regulate glycolysis can help clarify the therapeutic mechanisms these drugs use to inhibit liver disease.

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A Multichannel Metabolic Pathway Interference Strategy for Complete Energy Depletion‐Mediated Cancer Therapy

Ding,

Wei,

Fang

et al. 2024

Adv Funct Materials

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Hydrogen sulfide (H2S) is being progressively integrated as an emerging inhibitor of the electron transport chain in energy interference‐based tumor therapy. However, metabolic reprogramming in cancer cells causes both oxidative phosphorylation (OXPHOS) and glycolysis to occur simultaneously, which contributes to the ineffective therapeutic effect of blocking a single pathway. To achieve complete suppression of energy production, an inorganic H2S donor ZnS@ZIF‐8@CaP nanoparticle (ZSZC NP) carrying Ca and Zn is constructed for achieving simultaneous interference of OXPHOS and glycolysis. The core–shell ZSZC nanoparticles can break down in the tumor microenvironment. This leads to a sustained H2S release and calcium overload to disrupt the normal functioning of mitochondria by inhibiting the expression of cytochrome c and causing damage to mitochondrial membrane potential. Meanwhile, the presence of Zn2+ hinders the typical process of glycolysis by impeding the functioning of lactate dehydrogenase and glyceraldehyde‐3‐phosphate dehydrogenase. The synchronous interference of OXPHOS and glycolysis hampers the energy supply to cancer cells. Additionally, H2S and calcium overload can expedite tumor necrosis in vivo by inducing cellular acidification and calcification. Therefore, this energy‐blocking strategy will completely deplete the energy reserves of cancer cells and provide new insights for exploring bioenergetic inhibition as a treatment approach.

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Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Cited by 6 publications

References 429 publications

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype

Natural products target glycolysis in liver disease

A Multichannel Metabolic Pathway Interference Strategy for Complete Energy Depletion‐Mediated Cancer Therapy

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