scholarly journals Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-β–deficient neutrophils in a congenital neutropenia syndrome

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2783-2792 ◽  
Author(s):  
Hyun Sik Jun ◽  
Young Mok Lee ◽  
Yuk Yin Cheung ◽  
David H. McDermott ◽  
Philip M. Murphy ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nadph Oxidase ◽  
Energy Homeostasis ◽  
Glucose Transporter ◽  
Lactate Production ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Annexin V ◽  
Glucose Transporter 1 ◽  
Atp Production ◽  
Neutrophil Dysfunction

Abstract G6PC3 deficiency, characterized by neutropenia and neutrophil dysfunction, is caused by deficiencies in the endoplasmic reticulum (ER) enzyme glucose-6-phosphatase-β (G6Pase-β or G6PC3) that converts glucose-6-phosphate (G6P) into glucose, the primary energy source of neutrophils. Enhanced neutrophil ER stress and apoptosis underlie neutropenia in G6PC3 deficiency, but the exact functional role of G6Pase-β in neutrophils remains unknown. We hypothesized that the ER recycles G6Pase-β–generated glucose to the cytoplasm, thus regulating the amount of available cytoplasmic glucose/G6P in neutrophils. Accordingly, a G6Pase-β deficiency would impair glycolysis and hexose monophosphate shunt activities leading to reductions in lactate production, adenosine-5′-triphosphate (ATP) production, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Using annexin V–depleted neutrophils, we show that glucose transporter-1 translocation is impaired in neutrophils from G6pc3−/− mice and G6PC3-deficient patients along with impaired glucose uptake in G6pc3−/− neutrophils. Moreover, levels of G6P, lactate, and ATP are markedly lower in murine and human G6PC3-deficient neutrophils, compared with their respective controls. In parallel, the expression of NADPH oxidase subunits and membrane translocation of p47phox are down-regulated in murine and human G6PC3-deficient neutrophils. The results establish that in nonapoptotic neutrophils, G6Pase-β is essential for normal energy homeostasis. A G6Pase-β deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil dysfunction.

scholarly journals Up-regulation of key glycolysis proteins in cancer development

2018 ◽  
Vol 13 (1) ◽  
pp. 569-581
Author(s):  
Nicole Nowak ◽  
Anna Kulma ◽  
Jan Gutowicz
Keyword(s):  
Cancer Cells ◽  
Glucose Transporter ◽  
Lactate Production ◽  
Cancer Development ◽  
Glucose Transporter 1 ◽  
Expression Of Genes ◽  
Glycolysis Pathway ◽  
Cancer Cell Survival ◽  
Glycolytic Rate

AbstractIn rapid proliferating cancer cells, there is a need for fast ATP and lactate production, therefore cancer cells turn off oxidative phosphorylation and turn on the so called "Warburg effect". This regulating the expression of genes involved in glycolysis. According to many studies, glucose transporter 1, which supplies glucose to the cell, is the most abundantly expressed transporter in cancer cells. Hexokinase 2, is one of four hexokinase isoenzymes, is also another highly expressed enzyme in cancer cells and it functions to enhance the glycolytic rate. The up-regulation of these two proteins has been established as an important factor in promoting development and metastasis in many types of cancer. Furthermore, other enzymes involved in glycolysis pathway such as phosphoglucose isomerase and glyceraldehyde 3-phosphate dehydrogenase, exhibit additional functions in promoting tumor growth in a non-glycolytic way. This review demonstrates the pivotal role of GLUT1, HK2, PGI and GAPDH in cancer development. In particular, we look at how the multifunctional proteins, PGI and GAPDH, affect cancer cell survival. We also present various clinical cancer cases in terms of the overexpression of selected proteins, which may be considered as a therapeutic target.

scholarly journals Regulation of lactate production and glucose transport as well as of glucose transporter 1 and lactate dehydrogenase A mRNA levels by basic fibroblast growth factor in rat Sertoli cells

2002 ◽  
Vol 173 (2) ◽  
pp. 335-343 ◽  
Author(s):  
MF Riera ◽  
SB Meroni ◽  
HF Schteingart ◽  
EH Pellizzari ◽  
SB Cigorraga
Keyword(s):  
Growth Factor ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Lactate Production ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Short Term ◽  
Glucose Transporter 1 ◽  
Ldh Activity

By using cultured rat Sertoli cells as a model, both the action of basic fibroblast growth factor (bFGF) on lactate production and the site of this action were studied. bFGF stimulated Sertoli cell lactate production in a dose-dependent manner (basal: 7.3+/-0.5; 0.1 ng/ml bFGF: 7.5+/-0.5; 1 ng/ml bFGF: 7.5+/-0.6; 10 ng/ml bFGF: 10.3+/-1.0; 30 ng/ml bFGF: 15.2+/-1.5; 50 ng/ml bFGF: 15.4+/-1.6 microg/microg DNA). Two major sites for the action of this growth factor were identified. First, bFGF was shown to exert short- and long-term stimulatory effects on glucose transport (basal: 1170+/-102; 30 ng/ml bFGF for 120 min: 1718+/-152 and basal: 718+/-64; 30 ng/ml bFGF for 48 h: 1069+/-69 d.p.m./microg DNA respectively). Short-term bFGF stimulation of glucose transport was not inhibited by the protein synthesis inhibitor cycloheximide. These results indicate that short-term bFGF stimulation of glucose uptake does not involve an increase in the number of glucose transporters. On the other hand, stimulation with bFGF for periods of time longer than 12 h increased glucose transporter 1 (GLUT1) mRNA levels. These increased mRNA levels were probably ultimately responsible for the increments in glucose uptake that are observed in long-term treated cultures. Secondly, bFGF increased lactate dehydrogenase (LDH) activity (basal: 31.0+/-1.4; 30 ng/ml bFGF: 45.7+/- 2.4 mIU/microg DNA). The principal subunit component of those LDH isozymes that favors the transformation of pyruvate to lactate is subunit A. bFGF increased LDH A mRNA levels in a dose- and time-dependent manner. In summary, the results presented herein show that glucose transport, LDH activity and GLUT1 and LDH A mRNA levels are regulated by bFGF to achieve an increase in lactate production. These observed regulatory actions provide unequivocal evidence of the participation of bFGF in Sertoli cell lactate production which may be related to normal germ cell development.

BPIFB1 Inhibits Vasculogenic Mimicry Via Downregulation Of GLUT1-Mediated H3K27 Acetylation In Nasopharyngeal Carcinoma

2021 ◽  
Author(s):  
Xianjie Jiang ◽  
Xiangying Deng ◽  
Jie Wang ◽  
Yongzhen Mo ◽  
Lei Shi ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Glucose Transporter ◽  
Southern China ◽  
Vasculogenic Mimicry ◽  
Ectopic Expression ◽  
Lactate Production ◽  
Luciferase Reporter ◽  
Clinical Samples ◽  
Glucose Transporter 1

Abstract BackgroundNasopharyngeal carcinoma (NPC) exhibits significant regional differences and a high incidence in Southeast Asia and southern China. Bactericidal/permeability-increasing-fold-containing family B member 1 (BPIFB1) is a relatively specific and highly expressed protein in the nasopharyngeal epithelium. Accumulating evidence indicates that BPIFB1 is substantially downregulated in NPC and low BPIFB1 is associated with NPC patient’s poor prognosis. However, the clear molecular mechanism by which BPIFB1 regulates NPC is not well understood.MethodsThe expression of BPIFB1 was analyzed by immunohistochemistry(IHC) and the vasculogenic mimicry was examined by CD31/PAS double staining in NPC clinical samples. The regulation of BPIFB1 on vasculogenic mimicry in vitro and in vivo were performed by tube formation assay and xenograft assay respectively. ECAR was analyzed by Seahorse XF analyzer. 2-NBDG uptake was detected by FACS. Glucose consumption and lactate production were analyzed by Automatic Biochemical Analyzer. Downstream targets of BPIFB1 were validated by western blot, qPCR, Chip-qRT-PCR and dual luciferase reporter assay. Lastly, immunohistochemistry(IHC) was performed to confirm the relationship between BPIFB1 and related genes in NPC clinical samples. ResultsIn this study, we show that BPIFB1 plays an important role in regulating vasculogenic mimicry. Ectopic expression of BPIFB1 significantly inhibits vasculogenic mimicry. Mechanistically, we show that BPIFB1 can inhibits JNK/AP1 signaling which leads to inhibition of glucose transporter 1 (GLUT1) transcription and glycolysis, consequently, resulting in reducing histone H3K27 acetylation and decreasing the expression of vasculogenic mimicry-related VEGFA, VE-cadherin, and MMP2. ConclusionThis study demonstrates that BPIFB1 has a novel biological function in inhibiting glycolysis and vasculogenic mimicry and highlights that BPIFB1 is a potential target for NPC diagnosis and treatment.

Localisation and function of glucose transporter GLUT1 in chicken (Gallus gallus domesticus) spermatozoa: relationship between ATP production pathways and flagellar motility

2020 ◽  
Vol 32 (7) ◽  
pp. 697
Author(s):  
Rangga Setiawan ◽  
Chathura Priyadarshana ◽  
Atsushi Tajima ◽  
Alexander J. Travis ◽  
Atsushi Asano
Keyword(s):  
Oxidative Phosphorylation ◽  
Glucose Transporter ◽  
Response To Treatment ◽  
Mitochondrial Activity ◽  
Flagellar Motility ◽  
Glucose Transporter 1 ◽  
Atp Production ◽  
Potent Inhibition ◽  
Principal Piece ◽  
And Function

Glucose plays an important role in sperm flagellar motility and fertility via glycolysis and oxidative phosphorylation, although the primary mechanisms for ATP generation vary between species. The glucose transporter 1 (GLUT1) is a high-affinity isoform and a major glucose transporter in mammalian spermatozoa. However, in avian spermatozoa, the glucose metabolic pathways are poorly characterised. This study demonstrates that GLUT1 plays a major role in glucose-mediated motility of chicken spermatozoa. Using specific antibodies and ligand, we found that GLUT1 was specifically localised to the midpiece. Sperm motility analysis showed that glucose supported sperm movement during incubation for 0–80min. However, this was abolished by the addition of a GLUT1 inhibitor, concomitant with a substantial decrease in glucose uptake and ATP production, followed by elevated mitochondrial activity in response to glucose addition. More potent inhibition of ATP production and mitochondrial activity was observed in response to treatment with uncouplers of oxidative phosphorylation. Because mitochondrial inhibition only reduced a subset of sperm movements, we investigated the localisation of the glycolytic pathway and showed glyceraldehyde-3-phosphate dehydrogenase and hexokinase I at the midpiece and principal piece of the flagellum. The results of this study provide new insights into the mechanisms involved in ATP production pathways in avian spermatozoa.

scholarly journals Cancer Cells’ Metabolism Dynamics in Renal Cell Carcinoma Patients’ Outcome: Influence of GLUT-1-Related hsa-miR-144 and hsa-miR-186

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1733
Author(s):  
Mariana Morais ◽  
Francisca Dias ◽  
Inês Nogueira ◽  
Anabela Leão ◽  
Nuno Gonçalves ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Renal Cell ◽  
Glucose Transporter ◽  
Lactate Production ◽  
High Risk Group ◽  
Mrna Levels ◽  
Glucose Transporter 1 ◽  
Glut 1

The cancer cells’ metabolism is altered due to deregulation of key proteins, including glucose transporter 1 (GLUT-1), whose mRNA levels are influenced by microRNAs (miRNAs). Renal cell carcinoma (RCC) is the most common and lethal neoplasia in the adult kidney, mostly due to the lack of accurate diagnosis and follow-up biomarkers. Being a metabolic associated cancer, this study aimed to understand the hsa-miR-144-5p and hsa-miR-186-3p’s potential as biomarkers of clear cell RCC (ccRCC), establishing their role in its glycolysis status. Using three ccRCC lines, the intra- and extracellular levels of both miRNAs, GLUT-1’s mRNA expression and protein levels were assessed. Glucose consumption and lactate production were evaluated as glycolysis markers. A decrease of intracellular levels of these miRNAs and increase of their excretion was observed, associated with an increase of GLUT-1’s levels and glycolysis’ markers. Through a liquid biopsy approach, we found that RCC patients present higher plasmatic levels of hsa-miR-186-3p than healthy individuals. The Hsa-miR144-5p’s higher levels were associated with early clinical stages. When patients were stratified according to miRNAs plasmatic levels, low plasmatic levels of hsa-miR-144-5p and high plasmatic levels of hsa-miR-186-3p (high-risk group) showed the worst overall survival. Thus, circulating levels of these miRNAs may be potential biomarkers of ccRCC prognosis.

scholarly journals Deciphering the postsynaptic calcium-mediated energy homeostasis through mitochondria-endoplasmic reticulum contact sites using systems modeling

2020 ◽  
Author(s):  
A. Leung ◽  
D. Ohadi ◽  
G. Pekkurnaz ◽  
P. Rangamani
Keyword(s):  
Endoplasmic Reticulum ◽  
Energy Homeostasis ◽  
Atp Hydrolysis ◽  
Energy State ◽  
Reaction Diffusion ◽  
Differential Distribution ◽  
Spatiotemporal Model ◽  
Atp Production ◽  
Contact Sites ◽  
Reaction Diffusion Model

AbstractSpatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in post-synaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria, which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and differential distribution of key Ca2+ channels such as IP3 receptor and ryanodine receptor modulate Ca2+ dynamics in response to different stimuli. We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the cellular energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.

scholarly journals ER stress modulates cellular metabolism

2011 ◽  
Vol 435 (1) ◽  
pp. 285-296 ◽  
Author(s):  
Xiaoli Wang ◽  
Colins O. Eno ◽  
Brian J. Altman ◽  
Yanglong Zhu ◽  
Guoping Zhao ◽  
...  
Keyword(s):  
Er Stress ◽  
Glucose Transporter ◽  
Critical Role ◽  
Lactate Production ◽  
Cellular Metabolism ◽  
Metabolic Effects ◽  
Metabolic Processes ◽  
Glucose Transporter 1 ◽  
Haemopoietic Cells ◽  
Dying Cells

Changes in metabolic processes play a critical role in the survival or death of cells subjected to various stresses. In the present study, we have investigated the effects of ER (endoplasmic reticulum) stress on cellular metabolism. A major difficulty in studying metabolic responses to ER stress is that ER stress normally leads to apoptosis and metabolic changes observed in dying cells may be misleading. Therefore we have used IL-3 (interleukin 3)-dependent Bak−/−Bax−/− haemopoietic cells which do not die in the presence of the ER-stress-inducing drug tunicamycin. Tunicamycin-treated Bak−/−Bax−/− cells remain viable, but cease growth, arresting in G1-phase and undergoing autophagy in the absence of apoptosis. In these cells, we used NMR-based SIRM (stable isotope-resolved metabolomics) to determine the metabolic effects of tunicamycin. Glucose was found to be the major carbon source for energy production and anabolic metabolism. Following tunicamycin exposure, glucose uptake and lactate production are greatly reduced. Decreased 13C labelling in several cellular metabolites suggests that mitochondrial function in cells undergoing ER stress is compromised. Consistent with this, mitochondrial membrane potential, oxygen consumption and cellular ATP levels are much lower compared with untreated cells. Importantly, the effects of tunicamycin on cellular metabolic processes may be related to a reduction in cell-surface GLUT1 (glucose transporter 1) levels which, in turn, may reflect decreased Akt signalling. These results suggest that ER stress exerts profound effects on several central metabolic processes which may help to explain cell death arising from ER stress in normal cells.

scholarly journals Shenmai Injection Supresses Glycolysis and Enhances Cisplatin Cytotoxicity in Cisplatin-Resistant A549/DDP Cells via the AKT-mTOR-c-Myc Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ye Sun ◽  
Yushi Chen ◽  
Ming Xu ◽  
Chunying Liu ◽  
Hai Shang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Pyruvate Kinase ◽  
Glucose Transporter ◽  
A549 Cells ◽  
Lactate Production ◽  
Glycolytic Enzymes ◽  
Glucose Transporter 1 ◽  
Shenmai Injection ◽  
Expression Levels ◽  
Chemotherapy Drugs

Tumor cells, especially drug-resistant cells, predominately support growth by glycolysis even under the condition of adequate oxygen, which is known as the Warburg effect. Glucose metabolism reprogramming is one of the main factors causing tumor resistance. Previous studies on Shenmai injection (SMI), a Chinese herbal medicine, have shown enhanced efficacy in the treatment of tumors in combination with chemotherapy drugs, but the mechanism is not clear. In this study, we investigated the effect of SMI combined with cisplatin on cisplatin-resistant lung adenocarcinoma A549/DDP cells. Our results showed that cisplatin-resistant A549/DDP cells exhibited increased glucose consumption, lactate production, and expression levels of key glycolytic enzymes, including hexokinase 2 (HK2), pyruvate kinase M1/2 (PKM1/2), pyruvate kinase M2 (PKM2), glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA), compared with cisplatin-sensitive A549 cells. SMI combined with cisplatin in A549/DDP cells, led to significantly lower expression levels of key glycolytic enzymes, such as HK2, PKM1/2, GLUT1, and pyruvate dehydrogenase (PDH). In addition, we found that the combination of SMI and cisplatin could inhibit cell proliferation and promote apoptosis by reducing the expression levels of p-Akt, p-mTOR, and c-Myc, and then, it reduced the glycolysis level. These results suggest that SMI enhances the antitumor effect of cisplatin via glucose metabolism reprogramming. Therefore, the combination of SMI and cisplatin may be a potential therapeutic strategy to treat cisplatin-resistant nonsmall cell lung cancer.

scholarly journals Circ_0084043 promotes cell proliferation and glycolysis but blocks cell apoptosis in melanoma via circ_0084043-miR-31-KLF3 axis

2020 ◽  
Vol 15 (1) ◽  
pp. 774-786
Author(s):  
Songjiang Wu ◽  
Yuhan Tang ◽  
Wenli Liu
Keyword(s):  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Glucose Transporter ◽  
Lactate Production ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Glucose Transporter 1

AbstractMelanoma is an aggressive malignant tumor. The crucial role of circular RNAs has been documented in many types of cancer, including melanoma. The objective of this study was to uncover the function of circ_0084043 in the biological process of melanoma and associated mechanism of action. The expression of circ_0084043, miR-31, and Krüppel-like factor 3 (KLF3) was determined by qRT-PCR. Cell proliferation and apoptosis were monitored by the MTT assay and flow cytometry assay, respectively. The progression of glycolysis was evaluated according to the levels of glucose consumption, lactate production, and ATP concentration using appropriate detection kits. The relationship between miR-31 and circ_0084043 or KLF3 was predicted by the bioinformatics tool and ascertained by the dual-luciferase reporter assay. The protein levels of KLF3 and glucose transporter 1 (Glut1) were quantified by western blot. A xenograft model was established to ascertain the role of circ_0084043 in vivo. As a result, circ_0084043 expression was reinforced in melanoma tissues and cells. Circ_0084043 knockdown inhibited cell proliferation, induced cell apoptosis, and restrained glycolysis. MiR-31 was a target of circ_0084043, and miR-31 deficiency reversed the role of circ_0084043 knockdown. KLF3 was targeted by miR-31, and KLF3 upregulation abolished the effects of miR-31 enrichment. Moreover, circ_0084043 knockdown impeded tumor growth in vivo and suppressed the level of Glut1 by modulating miR-31 and KLF3. Circ_0084043 promoted cell proliferation and glycolysis, and blocked apoptosis through the circ_0084043–miR-31–KLF3 regulatory axis in melanoma.

scholarly journals Reversine, a selective MPS1 inhibitor, induced autophagic cell death via diminished glucose uptake and ATP production in cholangiocarcinoma cells

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10637
Author(s):  
Piya Prajumwongs ◽  
Orawan Waenphimai ◽  
Kulthida Vaeteewoottacharn ◽  
Sopit Wongkham ◽  
Kanlayanee Sawanyawisuth
Keyword(s):  
Cell Death ◽  
Glucose Uptake ◽  
Cell Lines ◽  
Glucose Transporter ◽  
Apoptotic Cell ◽  
Autophagic Cell Death ◽  
Glucose Transporter 1 ◽  
Atp Production ◽  
Mitotic Kinase ◽  
Monopolar Spindle

Reversine is a selective inhibitor of mitotic kinase monopolar spindle 1 (MPS1) and has been reported as an anticancer agent in various cancers. The effects of reversine on bile duct cancer, cholangiocarcinoma (CCA), a lethal cancer in Northeastern Thailand, were investigated. This study reports that reversine inhibited cell proliferation of CCA cell lines in dose- and time-dependent manners but had less inhibitory effect on an immortalized cholangiocyte cell line. Reversine also triggered apoptotic cell death by decreasing anti-apoptotic proteins, Bcl-XL and Mcl-1, increasing Bax pro-apoptotic protein and activating caspase-3 activity. Moreover, reversine induced autophagic cell death by increasing LC3-II and Beclin 1 while decreasing p62. Reversine activated autophagy via the AKT signaling pathway. Additionally, this study demonstrated for the first time that reversine could diminish the expression of Hypoxia-Inducible Factor 1- alpha (HIF-1α) and glucose transporter 1 (GLUT1), resulting in a reduction of glucose uptake and energy production in CCA cell lines. These findings suggest that reversine could be a good candidate as an alternative or supplementary drug for CCA treatment.

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