Glucose transporter isoform 1 (GLUT1) expression enhances formation and growth of hepatic metastases

AbstractInflammation plays central roles in the immune response. Inflammatory response normally requires higher energy and therefore is associated with glucose metabolism. Our recent study demonstrates that lncRNA HOTAIR plays key roles in NF-kB activation, cytokine expression, and inflammation. Here, we investigated if HOTAIR plays any role in the regulation of glucose metabolism in immune cells during inflammation. Our results demonstrate that LPS-induced inflammation induces the expression of glucose transporter isoform 1 (Glut1) which controls the glucose uptake in macrophages. LPS-induced Glut1 expression is regulated via NF-kB activation. Importantly, siRNA-mediated knockdown of HOTAIR suppressed the LPS-induced expression of Glut1 suggesting key roles of HOTAIR in LPS-induced Glut1 expression in macrophage. HOTAIR induces NF-kB activation, which in turn increases Glut1 expression in response to LPS. We also found that HOTAIR regulates glucose uptake in macrophages during LPS-induced inflammation and its knockdown decreases LPS-induced increased glucose uptake. HOTAIR also regulates other upstream regulators of glucose metabolism such as PTEN and HIF1α, suggesting its multimodal functions in glucose metabolism. Overall, our study demonstrated that lncRNA HOTAIR plays key roles in LPS-induced Glut1 expression and glucose uptake by activating NF-kB and hence HOTAIR regulates metabolic programming in immune cells potentially to meet the energy needs during the immune response.

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Estrogen and Progesterone Up-Regulate Glucose Transporter Expression in ZR-75-1 Human Breast Cancer Cells

Endocrinology ◽

10.1210/en.2003-0294 ◽

2003 ◽

Vol 144 (10) ◽

pp. 4527-4535 ◽

Cited By ~ 27

Author(s):

Rodolfo A. Medina ◽

Ana Maria Meneses ◽

Juan Carlos Vera ◽

Catherine Guzman ◽

Francisco Nualart ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Glucose Transporter ◽

Combined Therapy ◽

Hormone Replacement ◽

Breast Cancer Incidence ◽

Hormonal Treatment ◽

Glut1 Expression ◽

17Β Estradiol

Breast cancer incidence increases in women receiving combined estrogen and progesterone therapy. Breast tumors show increased expression of the glucose transporter GLUT1. We determined the effect of these hormones on GLUT1–4 expression and deoxyglucose transport in ZR-75-1 breast cancer cells. Immunoblotting, immunocytochemistry, flow cytometry, and RT-PCR showed that GLUT1 expression is up-regulated by progesterone and, to a greater degree, combined therapy. GLUT2 expression is unaffected by hormonal treatment. GLUT3 protein and RNA is up-regulated by progesterone and combined therapy, and GLUT4 protein expression is up-regulated by all hormonal treatments. Deoxyglucose transport studies revealed the presence of three transport components with characteristics corresponding to GLUT1/4, GLUT2, and GLUT3. 17β-Estradiol produced a slight increase in transport at the Michaelis constant (Km) corresponding to GLUT3. Progesterone produced a small increase in transport at the Km corresponding to GLUT1/4, and combined 17β-estradiol and progesterone produced a small increase in transport at the Km corresponding to GLUT3 and a large increase in transport at the Km corresponding to GLUT1/4. This indicates that 17β-estradiol and progesterone differentially regulate GLUT1–4 expression and that these changes correlate to changes in glucose uptake. We postulate that combined hormone replacement therapy provides a survival advantage to developing ZR-75 breast cancer cells.

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Selective chronic regulation of GLUT1 and GLUT4 content by insulin, glucose, and lipid in rat cardiac muscle in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.3.h1309 ◽

1997 ◽

Vol 273 (3) ◽

pp. H1309-H1316 ◽

Cited By ~ 8

Author(s):

D. R. Laybutt ◽

A. L. Thompson ◽

G. J. Cooney ◽

E. W. Kraegen

Keyword(s):

Cardiac Muscle ◽

Plasma Glucose ◽

Glucose Transporter ◽

Close Association ◽

Nonesterified Fatty Acid ◽

Control Group ◽

Dependent Manner ◽

Energy Status ◽

Glut1 Expression

The glucose transporter GLUT1 may play a more important role in cardiac than in skeletal muscle, but its regulation is unclear. During fasting, cardiac GLUT1 declines in the presence of low plasma insulin and glucose and high nonesterified fatty acid (NEFA) levels, whereas GLUT4 is unchanged. We investigated insulin, glucose, and NEFA levels as regulatory factors of cardiac GLUT content in chronically cannulated rats. Fasting rats were infused for 24 h with saline or insulin (2 rates) while plasma glucose was equalized by a glucose clamp; final transporter content was compared with a fed control group. There was a close association of GLUT1 content with insulin (r2 = 0.83, P < 0.001), with GLUT1 varying over a threefold range, under equivalent fasting glycemic conditions (plasma glucose, 5.1 +/- 0.1 mM). Maintenance of fed insulin levels during fasting prevented the GLUT1 fall (P < 0.01), whereas hyperinsulinemia (117 +/- 10 mU/l) led to significant overexpression of GLUT1 (155 +/- 12% of control, P < 0.01). When high glucose (7.6 +/- 0.1 mM) or high NEFA (0.76 +/- 0.05 mM) levels accompanied the hyperinsulinemia, upregulation of GLUT1 was blocked. GLUT1 content correlated with an estimate of cardiac glucose clearance across the groups. Cardiac GLUT4 content, hexokinase, and acyl-CoA synthase activities were unaffected by fasting, insulin, or substrate manipulation. In conclusion, insulin preferentially upregulates GLUT1 (but not GLUT4) in a dose-dependent manner in cardiac muscle in vivo, and substrate supply modulates this response, since upregulation can be effectively blocked by increased glucose or lipid availability. Therefore, both insulin exposure and energy status of cardiac muscle may be important determinants of cardiac GLUT1 expression.

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Hypoxic upregulation of glucose transporters in BeWo choriocarcinoma cells is mediated by hypoxia-inducible factor-1

AJP Cell Physiology ◽

10.1152/ajpcell.00075.2007 ◽

2007 ◽

Vol 293 (1) ◽

pp. C477-C485 ◽

Cited By ~ 78

Author(s):

Marc U. Baumann ◽

Stacy Zamudio ◽

Nicholas P. Illsley

Keyword(s):

Glucose Transport ◽

Oxygen Tension ◽

Glucose Transporter ◽

Cell Model ◽

Hypoxia Inducible Factor ◽

Trophoblast Cell ◽

Low Oxygen ◽

Bewo Cells ◽

Glut1 Expression ◽

Choriocarcinoma Cells

Placental hypoxia has been implicated in pregnancy pathologies, including fetal growth restriction and preeclampsia; however, the mechanism by which the trophoblast cell responds to hypoxia has not been adequately explored. Glucose transport, a process crucial to fetoplacental growth, is upregulated by hypoxia in a number of cell types. We investigated the effects of hypoxia on the regulation of trophoblast glucose transporter (GLUT) expression and activity in BeWo choriocarcinoma cells, a trophoblast cell model, and human placental villous tissue explants. GLUT1 expression in BeWo cells was upregulated by the hypoxia-inducing chemical agents desferroxamine and cobalt chloride. Reductions in oxygen tension resulted in dose-dependent increases in GLUT1 and GLUT3 expression. Exposure of cells to hypoxic conditions also resulted in an increase in transepithelial glucose transport. A role for hypoxia-inducible factor (HIF)-1 was suggested by the increase in HIF-1α as a result of hypoxia and by the increase in GLUT1 expression following treatment of BeWo with MG-132, a proteasomal inhibitor that increases HIF-1 levels. The function of HIF-1 was confirmed in experiments where the hypoxic upregulation of GLUT1 and GLUT3 was inhibited by antisense HIF-1α. In contrast to BeWo cells, hypoxia produced minimal increases in GLUT1 expression in explants; however, treatment with MG-132 did upregulate syncytial basal membrane GLUT1. Our results show that GLUTs are upregulated by hypoxia via a HIF-1-mediated pathway in trophoblast cells and suggest that the GLUT response to hypoxia in vivo will be determined not only by low oxygen tension but also by other factors that modulate HIF-1 levels.

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Hyperglycemia is Associated with Poor Survival in Primary Central Nervous System Lymphoma Patients

Tumori Journal ◽

10.5301/tj.5000590 ◽

2016 ◽

Vol 103 (3) ◽

pp. 272-278 ◽

Cited By ~ 1

Author(s):

Ayumi Debata ◽

Koichi Yoshida ◽

Kenta Ujifuku ◽

Haruna Yasui ◽

Kensaku Kamada ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Glucose Transporter ◽

Cox Regression ◽

Univariate Analysis ◽

Prognostic Significance ◽

Central Nervous System Lymphoma ◽

Poor Performance Status ◽

Poor Survival ◽

Glut1 Expression

Purpose Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma (NHL), and it has been postulated that metabolic disorder may contribute to NHL etiology. We retrospectively investigated the prognostic significance of hyperglycemia in patients with PCNSL. We evaluated glucose transporter type 1 (GLUT1) expression by immunohistochemistry and analyzed its association with hyperglycemia and survival. Methods The medical and neuroradiologic records of 50 patients with PCNSL at our institution over the past 15 years were analyzed. Patients were divided into 3 groups based on mean fasting plasma glucose (FPG) levels: normal (<110 mg/dL), prediabetes (110-125 mg/dL), and diabetes (≥126 mg/dL). We defined prediabetes and diabetes groups as hyperglycemia. Results Forty-four percent of patients were in the prediabetes and diabetes groups. One-year survival rates were 73%, 66%, and 43% in normal, prediabetes, and diabetes groups, respectively. Univariate analysis revealed that high age, female sex, poor performance status, high mean FPG, and monotherapy were associated with shorter survival. Multivariable Cox regression analyses showed that high mean FPG and monotherapy were significant predictors of shorter survival (p = 0.036 and p = 0.000, respectively). The GLUT1 immunohistopathologic staining was performed in 34 cases, 20 of which (58%) showed variable levels of GLUT1 expression at the cell membrane and/or cytoplasm. Prediabetes and diabetes groups had a higher percentage of GLUT1-positive cells compared with the normal group (p = 0.015). Conclusions These findings indicate that hyperglycemia is associated with poor survival. The putative biological mechanism might involve differential GLUT1 expression between hyperglycemic and normal states in patients with PCNSL.

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In the Absence of Apoptosis, Myeloid Cells Arrest When Deprived of Growth Factor, But Remain Viable by Consuming Extracellular Glucose

10.1101/198754 ◽

2017 ◽

Author(s):

Li Dong ◽

Boris Reljic ◽

Jen G. Cheung ◽

Elizabeth S. Ng ◽

Lisa M. Lindqvist ◽

...

Keyword(s):

Growth Factor ◽

Glucose Transporter ◽

Myeloid Cells ◽

Cell Types ◽

Term Survival ◽

Interacting Protein ◽

Extracellular Glucose ◽

Glut1 Expression ◽

High Concentrations

AbstractWithdrawal of the growth factor interleukin 3 from IL3-dependent myeloid cells causes them to undergo Bax/Bak1-dependent apoptosis, whereas factor-deprivedBax-/-Bak1-/-cells remain viable, but arrest and shrink. It was reported that withdrawal of IL3 fromBax-/-Bak1-/-cells caused decreased expression of the glucose transporter Glut1, leading to reduced glucose uptake, so that arrested cells required Atg5-dependent autophagy for long-term survival. In other cell types, a decrease in Glut1 is mediated by the thioredoxin-interacting protein Txnip, which is induced in IL3-dependent myeloid cells when growth factor is removed. We mutatedAtg5andTxnipby CRISPR/Cas9 and found that Atg5-dependent autophagy was not necessary for the long-term viability of cycling or arrestedBax-/-Bak1-/-cells, and that Txnip was not required for the decrease in Glut1 expression in response to IL3 withdrawal. Surprisingly, Atg5-deficientBax/Bak1double mutant cells survived for several weeks in medium supplemented with 10% fetal bovine serum (FBS), without high concentrations of added glucose or glutamine. When serum was withdrawn, the provision of an equivalent amount of glucose present in 10% FBS (~0.5 mM) was sufficient to support cell survival for more than a week, in the presence or absence of IL3. Thus,Bax-/-Bak1-/-myeloid cells deprived of growth factor consume extracellular glucose to maintain long-term viability, without a requirement for Atg5-dependent autophagy.

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Glucose transporter 1 (GLUT1) expression is associated with intestinal type of gastric carcinoma

Journal of Korean Medical Science ◽

10.3346/jkms.2000.15.4.420 ◽

2000 ◽

Vol 15 (4) ◽

pp. 420 ◽

Cited By ~ 14

Author(s):

Wan Seop Kim ◽

Young Youl Kim ◽

Se Jin Jang ◽

Kuchan Kimm ◽

Myeong Ho Jung

Keyword(s):

Gastric Carcinoma ◽

Glucose Transporter ◽

Intestinal Type ◽

Glucose Transporter 1 ◽

Glut1 Expression

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Immunohistochemical Expression of Melatonin Receptor MT1 and Glucose Transporter GLUT1 in Human Breast Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666181025125532 ◽

2019 ◽

Vol 18 (15) ◽

pp. 2110-2116 ◽

Cited By ~ 3

Author(s):

Tialfi B. de Castro ◽

André L. Mota ◽

Newton A. Bordin-Junior ◽

Dalisio S. Neto ◽

Debora A.P.C. Zuccari

Keyword(s):

Breast Cancer ◽

Poor Prognosis ◽

Glucose Transporter ◽

Good Prognosis ◽

High Expression ◽

Human Breast ◽

Luminal A ◽

Cancer Subtypes ◽

Glut1 Expression ◽

Negative Controls

Background: Breast cancer is a heterogeneous disease and is the leading cause of cancer-related deaths among women. Even after diagnosis, the prognosis cannot be concluded since patients can develop resistance to therapy, which favors tumor growth, invasion and metastasis. In recent years, research has focused on identifying significant markers that can be used to determine the prognosis. Melatonin can act through G protein– coupled MT1 receptor, which controls selected protein kinases, influences the levels of transcription factor phosphorylation, specific genes expression, proliferation, angiogenesis, cell differentiation, migration, and indirectly controls the transport of glucose in cancer cells. It is known that glucose enters the cells by glucose transporters, such as GLUT1 which shows wide tissue distribution and appears to be altered in human breast carcinoma. High GLUT1 expression is associated with increased malignant potential, invasiveness and poor prognosis in some cancers including breast cancer. Objective: The aim of this study was to evaluate the expression of MT1 receptor and GLUT1 in breast tumors and correlate with molecular subtypes and prognostic characteristics. Method: Protein expression was performed by an immunohistochemical procedure with specific antibodies and positive and negative controls. Results: We found that MT1 high expression was associated with good prognosis subtype (Luminal A), while GLUT1 high expression was related to poor prognosis subtype (triple-negative). In addition, we found high expression of MT1 in ER+ and the inverse in GLUT1 expression. GLUT1 is also highly expressed in tumor ≥20mm. Conclusion: These results indicate MT1 and GLUT1 as potential targets for breast cancer subtypes and prognosis.

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Glucose transporters control gene expression of aldose reductase, PKCα, and GLUT1 in mesangial cells in vitro

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.1.f97 ◽

1999 ◽

Vol 277 (1) ◽

pp. F97-F104 ◽

Cited By ~ 10

Author(s):

Douglas N. Henry ◽

Julia V. Busik ◽

Frank C. Brosius ◽

Charles W. Heilig

Keyword(s):

Aldose Reductase ◽

Matrix Protein ◽

Glucose Transporter ◽

Mesangial Cells ◽

Organ Damage ◽

Glucose Transporter 1 ◽

Protein Levels ◽

Protein Kinase Cα ◽

Glut1 Expression

The process linking increased glucose utilization and activation of metabolic pathways leading to end-organ damage from diabetes is not known. We have previously described rat mesangial cells that were transduced to constitutively express the facilitative glucose transporter 1 (GLUT1, MCGT1 cells) or bacterial β-galactosidase (MCLacZ, control cells). Glucose transport was rate limiting for extracellular matrix production in the MCGT1 cells. In the present work, we investigated the effect of GLUT1 overexpression in mesangial cells on aldose reductase (AR), protein kinase Cα (PKCα), and native GLUT1 transcript levels, to determine whether changes in GLUT1 alone could regulate their expression in the absence of high extracellular glucose concentrations. MCGT1 cells grown in normal (8 mM) or elevated (20 mM) glucose had elevated abundance of AR, PKCα, and the native GLUT1 transcripts compared with control cells. AR protein levels, AR activity, sorbitol production, and PKCα protein content were also greater in the MCGT1 cells than in control cells grown in the same media. This is the first report of the concomitant activation of AR, PKCα, and GLUT1 genes by enhanced GLUT1 expression. We conclude that increased GLUT1 expression leads to a positive feedback of greater GLUT1 expression, increased AR expression and activity with polyol accumulation, and increased total and active PKCα protein levels, which leads to detrimental stimulation of matrix protein synthesis by diabetic mesangial cells.

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