Glucose Transporter Type 1 Expression Research Articles

GLUT1 promotes cell proliferation via binds and stabilizes phosphorylated EGFR in lung adenocarcinoma

BackgroundWhile previous studies have primarily focused on Glucose transporter type 1 (GLUT1) related glucose metabolism signaling, we aim to discover if GLUT1 promotes tumor progression through a non-metabolic pathway.MethodsThe RNA-seq and microarray data were comprehensively analyzed to evaluate the significance of GLUT1 expression in lung adenocarcinoma (LUAD). The cell proliferation, colony formation, invasion, and migration were used to test GLUT1 ‘s oncogenic function. Co-immunoprecipitation and mass spectrum (MS) were used to uncover potential GLUT1 interacting proteins. RNA-seq, DIA-MS, western blot, and qRT-PCR to probe the change of gene and cell signaling pathways.ResultsWe found that GLUT1 is highly expressed in LUAD, and higher expression is related to poor patient survival. GLUT1 knockdown caused a decrease in cell proliferation, colony formation, migration, invasion, and induced apoptosis in LUAD cells. Mechanistically, GLUT1 directly interacted with phosphor-epidermal growth factor receptor (p-EGFR) and prevented EGFR protein degradation via ubiquitin-mediated proteolysis. The GLUT1 inhibitor WZB117 can increase the sensitivity of LUAD cells to EGFR-tyrosine kinase inhibitors (TKIs) Gefitinib.ConclusionsGLUT1 expression is higher in LUAD and plays an oncogenic role in lung cancer progression. Combining GLUT1 inhibitors and EGFR-TKIs could be a potential therapeutic option for LUAD treatment.

The role of glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) expression by prostate adenocarcinoma tissue in determining disease prognosis and effectiveness of radical treatment

Introduction. Today, due to the insufficient diagnostic accuracy of existing tools for determining clinically significant forms of prostate cancer, the search for new indicators that predict the course of the disease and the effectiveness of radical treatment is relevant. Various malignant tumors could increase glucose consumption and grow under hypoxic conditions. It seems promising to assess the expression level of glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) in prostate adenocarcinoma cells of different malignancy score.Objective. To determine CAIX and GLUT1 expression in ISUP grades 1-5 prostate adenocarcinoma cells for evaluation of the disease prognosis and radical prostatectomy effectiveness.Materials and methods. Immunohistochemical study of postoperative material after radical prostatectomy with determination of GLUT1 and CAIX expression by tumor cells was carried out. The presence or absence of biochemical recurrence within one year after surgery was determined. The correlation between the level of expression, the presence of biochemical relapse and a few other clinical parameters was determined.Results. GLUT1 expression level statistically significant correlated with ISUP 4 and 5 (r = 0.457, p < 0.0001), prostate-specific antigen (PSA) level (r = 0.378, p < 0.0001), pT3b disease stage (r = 0.380, p < 0.0001), extracapsular extension (r = 0.355, p = 0.001), and inversely correlated with ISUP 1 (r = -0.274, p = 0.009). CAIX immunoexpression was observed in 10.0% of samples and the intensity was low (< 20% of cells).Conclusion. Elevated expression of glucose transporter type 1 (GLUT1) by prostate adenocarcinoma cells among patients after radical prostatectomy is associated with high grade of malignancy (ISUP 4 and 5), pT3b disease stage, extracapsular extension of the tumor, as well as high PSA, which allows using it for the prognosis evaluation.

Decreased expression of Glucagon-like peptide-1 receptor and Sodium-glucose co-transporter 2 in patients with proliferative diabetic retinopathy.

To investigate the expression of Glucagon-like peptide-1 receptor (GLP-1R), sodium-glucose co-transporter (SGLT) 1, SGLT2, Glucose transporter type 1 (GLUT1) and GLUT2 in patients with diabetic retinopathy (DR). We obtained peripheral blood mononuclear cells (PBMCs) and vitreous samples from 26 proliferative DR (PDR) patients, 25 non-proliferative DR (NPDR) patients, 25 non-DR (NDR) patients, and 26 nondiabetic patients with idiopathic epiretinal membranes (ERMs, control). The protein level and mRNA expression level of GLP-1R were quantified by immunoblot and qRT-PCR and the levels of SGLT1, SGLT2, GLUT1, and GLUT2 expression were determined by PCR. Their association with clinical parameters and PBMCs/vitreous cytokine was analyzed. Furthermore, immunofluorescence staining of GLP-1R and SGLT2 was carried out on samples of fibrovascular membranes (FVMs) retrieved from 26 patients with PDR and 26 patients with ERMs. The transcriptional levels of GLP-1R and SGLT2 in PBMCs were significantly more decreased in PDR patients than in patients without DR and controls, which was simultaneously associated with an increased level of expression of tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The expression levels of GLUT1 and GLUT2 were tightly correlated with their SGLT partners, respectively. Further, Immunofluorescence staining showed no positive staining of GLP-1R and SGLT2 was detected in the FVMs from PDR. GLP-1R and SGLT2 were significantly decreased in PDR patients which was associated with an increased level of expression of TNF-α and IFN-γ. These findings implicate that defective GLP-1R and SGLT2 signaling may potentially correlate with immune response cytokines in patients with PDR.

Arginine ADP-ribosyltransferase 1 Regulates Glycolysis in Colorectal Cancer via the PI3K/AKT/HIF1α Pathway

ObjectiveArginine ADP-ribosyltransferase 1 (ART1) is involved in the regulation of a diverse array of pathophysiological processes, including proliferation, invasion, apoptosis, autophagy and angiogenesis of colorectal cancer (CRC) cells. However, how ART1 regulates glycolysis in CRC remains elusive.MethodsTo elucidate the role of ART1 in glycolysis in CRC, we assessed the protein level of ART1, hypoxia-inducible factor 1α (HIF1α), and glucose transporter type 1 (GLUT1) in 61 CRC tumor tissue specimens obtained from patients with different 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake as analyzed by PET/CT before surgery. Colon adenocarcinoma CT26 cells with ART1 knockdown and overexpression were established, respectively, and the molecular mechanism underlying the effect of ART1 on glycolysis in CRC was determined both in vivo and in vitro.ResultsThe expression of ART1 and GLUT1 was significantly associated with FDG uptake (P=0.037 and P=0.022, respectively) in CRC tissues. Furthermore, the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH) was upregulated in ART1-overexpressed CT26 cells, but was downregulated in ART1-knockdown CT26 cells. The volume and weight of subcutaneously transplanted tumors were markedly increased in the ART1-overexpressed BALB/c mice group and decreased in the ART1-knockdown group. In CT26 cells, the overexpression of ART1 promoted the expression levels of HK2 and LDH, and knockdown of ART1 suppressed them in the CT26 tumors. In both normal and hypoxic conditions, ART1 expression was associated with the protein level of phospho-serine/threonine kinase (p-AKT), HIF1α, and GLUT1 but not with that of AKT in CT26 cells and subcutaneous transplanted tumors.ConclusionART1 plays a crucial role in the elevation of glucose consumption in CT26 cells and may regulate GLUT1-dependent glycolysis in CRC via the PI3K/AKT/HIF1α pathway.

SIRT5 is involved in the proliferation and metastasis of breast cancer by promoting aerobic glycolysis

ObjectiveBreast cancer (BC) is the most commonly diagnosed cancer among females and has a poor prognosis, breast invasive ductal carcinoma is the most common histological type. The occurrence and development of BC is closely related to aberrant glucose metabolism. In the hyperglycemic environment caused by abnormal glucose metabolism, hypoxia-inducible factor-1 alpha (HIF-1α) enables tumor cells to absorb large amounts of glucose and enhance glycolysis by inducing the expression of glucose transporter type1 (GLUT1) and glycolysis genes, thus promoting tumor cell proliferation and metastasis. Mitochondrial Sirtuin5 (SIRT5) plays a role in the rewiring of glucose metabolism during the progression of cancers. Thus, we aimed to elucidate whether SIRT5 promotes BC proliferation and metastasis by facilitating aerobic glycolysis in BC. MethodsThe expression of SIRT5 in breast carcinoma tissue and cells was evaluated using immunohistochemical staining, western blot and quantitative reverse transcription-polymerase chain reaction (qRT–PCR) analysis to confirm the biological role of SIRT5 in breast carcinoma. We established a stable cell line with SIRT5 knockdown using lentiviral transduction in T47D cells to reduce SIRT5 expression and then evaluated the effect of SIRT5 on cells cultured in the presence of high glucose (4500 mg/L) and normal glucose (2000 mg/L) concentrations. Cell proliferation was detected using the CCK-8 assay, the cell cycle and cell apoptosis were measured using flow cytometry and Annexin V staining, and cell migration was tested by performing Celigo scratch and Transwell assays. The expression of PKM2, HK2, mTOR and HIF-1α, which play roles in aerobic glycolysis, was investigated using western blot. ResultsSIRT5 was overexpressed in BC tissues compared with paired normal tissues. Prognostic and OS analyses showed that the SIRT5 expression level was an individual prognostic factor for patients with BC. SIRT5 knockdown inhibited proliferation and metastasis and slightly increased apoptosis in T47D cells under high-glucose conditions. Furthermore, the downregulation of HK2 and HIF-1α caused by SIRT5 knockdown was a high glucose-dependent process, while the downregulation of PKM2 was mediated by a high glucose-independent process. ConclusionsSIRT5 is an independent prognostic factor for BC and contributes to cell proliferation and metastasis in a high glucose-dependent manner to some degree, which might be mediated by promoting aerobic glycolysis.

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma.

BAY-876 is an effective antagonist of the Glucose transporter type 1 (GLUT1) receptor, a mediator of aerobic glycolysis, a biological process considered a hallmark of hepatocellular carcinoma (HCC) together with cell proliferation, drug-resistance, and metastasis. However, the clinical application of BAY-876 has faced many challenges. In the presence study, we describe the formulation of a novel microcrystalline BAY-876 formulation. A series of HCC tumor models were established to determine not only the sustained release of microcrystalline BAY-876, but also its long-acting antitumor activity. The clinical role of BAY-876 was confirmed by the increased expression of GLUT1, which was associated with the worse prognosis among advanced HCC patients. A single dose of injection of microcrystalline BAY-876 directly in the HCC tissue achieved sustained localized levels of Bay-876. Moreover, the single injection of microcrystalline BAY-876 in HCC tissues not only inhibited glucose uptake and prolonged proliferation of HCC cells, but also inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors. Thus, the microcrystalline BAY-876 described in this study can directly achieve promising localized effects, given its limited diffusion to other tissues, thereby reducing the occurrence of potential side effects, and providing an additional option for advanced HCC treatment.

The Ang III/AT2R Pathway Enhances Glucose Uptake by Improving GLUT1 Expression in 3T3-L1 Adipocytes

Angiotensin III (Ang III) is a heptapeptide derived from Ang II that has been confirmed as the preferred agonist of angiotensin II type 2 receptor (AT2R). Recent studies have revealed AT2R mainly exerts anti-inflammation effects. However, the effects of the Ang III/AT2R pathway on adipocytes remain unknown. Here, the effects of Ang III on glucose uptake were examined. The results showed that AT2R expression was upregulated during adipogenesis in 3T3-L1 preadipocytes, whereas AT1R expression was diminished. Also, Ang III (10 nM) significantly increased glucose uptake by 3T3-L1 adipocytes, which was blocked by PD123319, an AT2R blocker, but not by irbesartan, an AT1R blocker. Ang III also induced the expression of glucose transporter type 1 (GLUT1). These stimulatory effects were inhibited by pretreatment with PD123319, but not with irbesartan. Together, these results indicate that Ang III enhances glucose uptake by upregulating GLUT1 expression via AT2R.

Prognostic significance of hypoxia-inducible factor-1α expression in advanced pharyngeal cancer without human papillomavirus infection.

This study aimed to clarify the association between both hypoxia-inducible factor-1α and glucose transporter type-1 expression and survival outcome in advanced pharyngeal cancer without human papillomavirus infection. Twenty-five oropharyngeal and 55 hypopharyngeal cancer patients without human papillomavirus infection were enrolled. All patients had stage III-IV lesions and underwent concurrent chemoradiotherapy or surgery. Hypoxia-inducible factor-1α and glucose transporter type-1 expression were investigated in primary lesions by immunohistochemistry. There were 41 and 39 cases with low and high hypoxia-inducible factor-1α expression, and 28 and 52 cases with low and high glucose transporter type-1 expression, respectively. There was no significant correlation between hypoxia-inducible factor-1α and glucose transporter type-1 expression. In univariate analysis, nodal metastasis, clinical stage and high hypoxia-inducible factor-1α expression, but not glucose transporter type-1 expression, predicted significantly worse prognosis. In multivariate analysis, hypoxia-inducible factor-1α overexpression was significantly correlated with poor overall survival, disease-specific survival and recurrence-free survival. High hypoxia-inducible factor-1α expression was an independent risk factor for poor prognosis for advanced human papillomavirus-unrelated pharyngeal cancer.

LRP1 mediates the IGF-1-induced GLUT1 expression on the cell surface and glucose uptake in M\xfcller glial cells

Insulin-like Growth Factor-1 (IGF-1) is involved in the normal development and survival of retinal cells. Low-density lipoprotein Receptor-related Protein-1 (LRP1) plays a key role on the regulation of several membrane proteins, such as the IGF-1 receptor (IGF-1R). In brain astrocytes, LRP1 interact with IGF-1R and the glucose transporter type 1 (GLUT1), regulating the glucose uptake in these cells. Although GLUT1 is expressed in retinal Müller Glial Cells (MGCs), its regulation is not clear yet. Here, we investigated whether IGF-1 modulates GLUT1 traffic to plasma membrane (PM) and glucose uptake, as well as the involvement of LRP1 in this process in the human Müller glial-derived cell line (MIO-M1). We found that IGF-1 produced GLUT1 translocation to the PM, in a time-dependent manner involving the intracellular signaling activation of MAPK/ERK and PI3K/Akt pathways, and generated a significant glucose uptake. Moreover, we found a molecular association between LRP1 and GLUT1, which was significantly reduced by IGF-1. Finally, cells treated with specific siRNA for LRP1 showed an impaired GLUT1 expression on PM and decreased glucose uptake induced by IGF-1. We conclude that IGF-1 regulates glucose homeostasis in MGCs involving the expression of LRP1.

GLUT-1 as a predictor of worse prognosis in pancreatic adenocarcinoma: immunohistochemistry study showing the correlation between expression and survival

BackgroundVarious parameters have been considered for predicting survival in pancreatic ductal adenocarcinoma. Information about western population is missing. The aim of this study is to assess the association between Glucose transporter type 1 (GLUT-1) expression and prognosis for patients with PDAC submitted for surgical resection in a European cohort.MethodsRetrospective analysis of PDAC specimens after pancreatoduodenectomy assessing GLUT-1 expression according to intensity (weak vs strong) and extension (low if < 80% cells were stained, high if > 80%) was performed. Statistical analysis was performed using the exact Fisher test, Student t test or the Mann-Whitney U test. Survival was analysed using the Kaplan-Meier method and compared with the Log-rank test. The differences were considered significant at a two-sided p value of < 0.05. All statistical analyses were performed using SPSS® 23.0 for Windows (SPSS Inc., Chicago, IL, USA).ResultsOur study consisted of 39 patients of which 58.9% presented with weak and 41.1% with strong intensity. The median extension was 90%: 28.2% cases presented with a low extension and 71.8% with a high extension. No significant differences related to intensity were found. The high-extension group showed a higher percentage of T3 PDAC (92.9% vs 63.6%, p = 0.042) and LNR20 (35.7% vs 0%, p = 0.037) as well as shorter disease-free survival (17.58 vs 54.46 months; p = 0.048).ConclusionsOur findings suggest that GLUT-1 could be related to higher aggressivity in PDAC and could be used as a prognostic marker, identifying patients with a worse response to current therapies who could benefit from more aggressive treatments.

Diagnostic value of 18F-FDG-PET to predict the tumour immune status defined by tumoural PD-L1 and CD8+tumour-infiltrating lymphocytes in oral squamous cell carcinoma

BackgroundLately, immune checkpoint proteins, such as programmed death 1 (PD-1) and its ligand-1 (PD-L1), have garnered attention as a new target in oral squamous cell carcinoma (OSCC). Reportedly, fluoro-d-glucose (FDG)-uptake alteration by anti-PD-1 antibody treatment depicts the response in patients with lung cancer. This study aims to elucidate the correlations between tumour immune status, clinicopathological factors, 18F-FDG-uptake and cold tumour phenotypes as low PD-L1 expression/low CD8+tumour-infiltrating lymphocytes (TILs) in OSCC.MethodsWe performed immunohistochemical analysis of PD-L1, hypoxia-inducible factor 1 A (HIF-1A), glucose transporter type 1 (GLUT1), CD8, E-cadherin and Ki-67 on 59 operable OSCC samples. We assessed the correlations between these factors and preoperative 18F-FDG-uptake, clinicopathological characteristics and prognosis.ResultsLow expression of PD-L1 in OSCC correlated with cancer aggressiveness, poor prognosis, high 18F-FDG-uptake with HIF-1A/GLUT1 and low E-cadherin expression and low CD8. Cold tumour phenotypes as low PD-L1 tumour cells and low stromal CD8 correlated with the poor prognosis, high 18F-FDG-uptake and E-cadherin suppression. Furthermore, the high level of preoperative 18F-FDG-uptake in OSCC was an independent predictor of the cold tumour immune status.Conclusions18F-FDG-uptake is an independent predictor of cold tumour in OSCC. 18F-FDG-PET imaging could be a promising diagnostic tool to estimate tumour immune status.

18F]fluorodeoxyglucose-positron emission tomography and glucose-transporter type 1 expression in untreated primary small bowel adenocarcinoma.

Literature reporting [18F]fluorodexoyglucose positron emission tomography (FDG-PET) of small bowel adenocarcinoma, a rare tumor, is sparse. To assess FDG uptake in small bowel adenocarcinoma, we retrospectively analyzed a large, single-center database and determined the expression of glucose-transporter type 1 (GLUT-1). Screening of PET datasets in the database (N.=28,961 scans) for untreated histologically-confirmed primary small bowel adenocarcinoma revealed evaluable PET datasets for eight patients. Maximum and peak standardized uptake values (SUV<inf>max</inf> and SUV<inf>peak</inf>, respectively) were calculated via volume-of-interest (VOI) analysis. Additionally, GLUT-1 expression on tumor specimens was prospectively immunohistochemically assessed. All primary tumors showed high FDG uptake: mean SUVmax was 9.5±2.6 (range: 5.0-13.0) and SUVpeak, 8.1±2.3 (range: 3.9-10.7). Corresponding biopsy specimens (N.=7) demonstrated high GLUT-1 expression. Primary small bowel adenocarcinomas have a high GLUT-1 expression. Tumor lesions consistently demonstrated high FDG uptake pre-treatment, suggesting FDG-PET utility in staging and follow-up of these tumors.

Mechanisms of antimelanoma effect of oat β-glucan supported by electroporation

There are still not specified mechanisms how beta-glucan molecules are transported into cells. Supposing, beta-glucan toxicity against tumor cells may be related to the overexpression of the transporter responsible for the transport of glucose molecules in the cells. In this case, glucans - polymers composed of glucose units are much more up-taken by tumor than normal cells. Increased GLUT1 (Glucose Transporter Type 1) expression has been demonstrated earlier in malignant melanomas. GLUT1 expression promotes glucose uptake and cell growth in that cells. Also, in human melanoma tissues a significant correlation between GLUT1 expression and mitotic activity was found.The aim of the study was to verify if oat β-glucan (OβG) is delivered into cells by GLUT-1 membrane protein. To check it out we blocked GLUT1 transporters by an inhibitor WZB117 and then we investigated cells viability with and without reversible electroporation (EP).The obtained results bring us to elucidate the mechanism of transport of the OβG into the cells is GLUT-1 dependent and moreover can be supported by EP method.

Gene therapy for Glut1-deficient mouse using an adeno-associated virus vector with the human intrinsic GLUT1 promoter.

We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene, encoding glucose transporter type 1 (GLUT1), was expressed under the human endogenous GLUT1 promoter (AAV-GLUT1). We examined whether AAV-GLUT1 administration could lead to functional improvement in GLUT1-deficient mice. We extrapolated human endogenous GLUT1 promoter sequences from rat minimal Glut1 promoter sequences. We generated a tyrosine-mutant AAV9/3 vector in which human SLC2A1-myc-DDK was expressed under the human GLUT1 promoter (AAV-GLUT1). AAV-GLUT1 was administered to GLUT1-deficient mice (GLUT1+/- mice) via intracerebroventricular injection (1.85 × 1010 vg/mouse or 6.5 × 1010 vg/mouse). We analyzed exogenous GLUT1 mRNA and protein expression in the brain and other major organs. We also examined improvements of cerebral microvasculature, motor function using rota-rod and footprint tests, as well as blood and cerebrospinal fluid (CSF) glucose levels. Additionally, we confirmed exogenous GLUT1 protein distribution in the brain and other organs after intracardiac injection (7.8 × 1011 vg/mouse). Exogenous GLUT1 protein was strongly expressed in the cerebral cortex, hippocampus and thalamus. It was mainly expressed in endothelial cells, and partially expressed in neural cells and oligodendrocytes. Motor function and CSF glucose levels were significantly improved following intracerebroventricular injection. Exogenous GLUT1 expression was not detected in other organs after intracerebroventricular injection of AAV-GLUT1, whereas it was detected in the liver and muscle tissue after intracardiac injection. Exogenous GLUT1 expression after AAV-GLUT1 injection approximated that of physiological human GLUT1 expression. Local central nervous system administration of AAV-GLUT1 improved CSF glucose levels and motor function of GLUT1-deficient mice and minimized off-target effects.

Significance of Glucose Transporter Type 1 (GLUT-1) Expression in the Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma.

This study aimed to examine the prognostic relevance of glucose transporter type 1 (GLUT-1), which is a key regulator of the glucose metabolism. In particular, the study aimed to examine the association between GLUT-1 expression and the therapeutic effect of chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC were enrolled in the study. Patients with distant metastases and those who received only chemotherapy as treatment were excluded from the study. Specimens for immunohistochemical evaluations were obtained through surgical resection and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the primary tumor before any treatment. This study included 197 patients. Of these 197 patients, 100 underwent upfront surgery, and 97 received neoadjuvant CRT (NACRT), which was performed mainly for patients with locally advanced tumors. Of the 97 patients who received NACRT, 21 later underwent surgical resection. For the patients who underwent upfront surgery, low GLUT-1 expression was an independent factor for a better prognosis. For the patients who underwent NACRT, low GLUT-1 expression was significantly associated with greater tumor size reduction, a higher resection rate, and a better prognosis. Additionally, GLUT-1 expression was significantly increased after NACRT treatment. Among the patients with PDAC, those with low GLUT-1 expression in the primary tumor had a better prognosis those with high GLUT-1 expression. Moreover, the patients with low GLUT-1 expression displayed a better therapeutic response to NACRT.

A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome.

Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1‐DS) leads to a wide range of neurological symptoms. Ketogenic diets are very efficient to control epilepsy and movement disorders. We tested a novel simple and rapid blood test in 30 patients with GLUT1‐DS with predominant movement disorders, 18 patients with movement disorders attributed to other genetic defects, and 346 healthy controls. We detected significantly reduced GLUT1 expression only on red blood cells from patients with GLUT1‐DS (23 patients; 78%), including patients with inconclusive genetic analysis. This test opens perspectives for the screening of GLUT1‐DS in children and adults with cognitive impairment, movement disorder, or epilepsy. Ann Neurol 2017;82:133–138

P2.01-028 Prognostic Significance of GLUT1 and CAIX Expression: Correlation with Volume-Based PET Parameters in Non-Small Cell Lung Cancer

Glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) represent glucose metabolism and tissue hypoxia, respectively. The purpose of this study is to measure the GLUT1 and CAIX expression and volume-based 18F-fluorodeoxyglucose positron emission tomography (FDG PET) parameters in non-small cell lung cancer (NSCLC) patients and examined the correlations between above parameters and their prognostic significance. We evaluated GLUT1 and CAIX expression by immunohistochemical methods and volume-based FDG PET parameters in 269 NSCLC patients treated with surgical resection (158 adenocarcinoma, 93 squamous cell carcinoma and 18 other type carcinoma). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of NSCLC were measured using pretreatment 18F-FDG PET/CT. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of MTV or TLG. Correlations between GLUT1, CAIX, MTV, TLG, and clinicopathological factors were assessed, and prognostic significance was determined. The GLUT1 expression was identified in 99% of squamous cell carcinoma and 50% of adenocarcinoma. In patients with adenocarcinoma, GLUT1 expression showed positive correlation with MTV or TLG (P = 0.012 and P = 0.037, respectively). In patients with squamous cell carcinoma, correlation analyses between GLUT1, MTV and TLG were not performed because most cases of squamous cell carcinoma showed GLUT1 positivity. There was no correlation between CAIX expression, MTV and TLG in squamous cell carcinoma and adenocarcinoma. In cases with adenocarcinoma, GLUT1-positive patients had lower overall survival (OS) rates and lower recur-free survival (RFS) rates than GLUT1-negative patients (P < 0.001 and P = 0.004, respectively). CAIX expression was not significantly associated with either OS or RFS in squamous cell carcinoma and adenocarcinoma. Patients with high MTV or TLG had significantly lower OS rates and lower RFS rates than patients with low MTV or TLG in adenocarcinoma. High GLUT1, TLG and MTV were significantly associated with adverse clinicopathologic variables. When patients with adenocarcinoma were stratified into two groups (High GLUT1 and TLG vs. the other 3 groups), high GLUT1 and TLG was an independent prognostic marker for OS in multivariate analysis (P = 0.003). Our results show that high GLUT1 expression levels were significantly associated with MTV or TLG in patients with adenocarcinoma. High GLUT1 and TLG was an independent prognostic marker for OS. High GLUT1 and TLG can be used to identify a subgroup of patients with adenocarcinoma at high risk of recurrence or progression who may benefit from aggressive chemotherapy or radiotherapy.

Hyperglycemia is associated with poor survival in primary central nervous system lymphoma patients.

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. 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. 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). 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.

Differential expression and prognostic significance of GLUT1 according to histologic type of non-small-cell lung cancer and its association with volume-dependent parameters

BackgroundWe evaluated glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) expression, together with volume-based18F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters, in non-small cell lung cancer (NSCLC) patients, and examined the prognostic significance of those parameters according to its histologic subtype. MethodA total of 269 patients, who underwent surgical resection for NSCLC, were reviewed retrospectively. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) values were measured by preoperative 18F-fluorodeoxyglucose positron emission tomography computed tomography. GLUT1 and CAIX expression was evaluated using immunohistochemical method. ResultsThe mean MTV and TLG values were 30.0±57.1 and 165.4±361.3, respectively, and were significantly higher in patients with squamous cell carcinoma than with adenocarcinoma (p=0.047 for MTV; p=0.042 for TLG). GLUT1 expression was identified in 99% of squamous cell carcinoma and 50% of adenocarcinoma patients. MTV and TLG values were significantly higher in GLUT1-positive than GLUT-negative adenocarcinomas; however, CAIX expression did not show this pattern. GLUT1-positive adenocarcinoma patients had a lower OS than GLUT1-negative patients (p<0.001), whereas CAIX-positive and CAIX-negative patients showed similar OS rates (p=0.226). Patients with high MTV and TLG values showed lower OS rates than those with low MTV and TLG values. Multivariate analysis showed that GLUT1 positivity was an independent risk factor for a lower OS rate in lung adenocarcinoma patients (hazard ratio=2.574, p=0.016). GLUT1 expression was associated with micropapillary/solid histology, lymphovascular invasion, and advanced pTNM stage. ConclusionsMTV and TLG values, and GLUT1 expression, significantly differed between patients with squamous cell carcinoma and adenocarcinoma. High GLUT1 expression levels were significantly associated with MTV and TLG values and adverse clinical outcomes in patients with adenocarcinoma.

Regulation of bone homeostasis by glucose

Synthesis of type Ⅰ collagen, a major component of the bone matrix, precedes the expression of Runt-related transcription factor 2(Runx2), a master regulator in osteoblast differentiation. Thus, a direct link between osteoblast differentiation and bone formation is seemingly absent, and how these are maintained in a coordinated matter remains unclear. It was recently demonstrated that osteoblasts depend on glucose, which glucose transporter type 1(GLUT1)takes up as an energy source, and it was found that glucose uptake promotes osteoblast differentiation and bone formation via AMP-activated protein kinase. It was also shown that Runx2 upregulates GLUT1 expression, and this Runx2-GLUT1 feedforward regulation integrates and coordinates osteoblast differentiation and bone formation throughout life. These previous findings revealed that the energy metabolism balance in osteoblasts integrates the differentiation and function of osteoblasts, and re-emphasized the importance of crosstalk between bone and sugar metabolism.