Inhibition Of Glucose Transporter 1 Research Articles

TMIC-17. TARGETING THE FLUIDIC FORCE-SENSING MECHANISM TO TREAT BRAIN TUMOR METASTASIS

Abstract Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in tissue microenvironment. How brain tumor growth alters the conduit of biofluid, thereby impacting FSS-regulated cancer progression is unknown. Medulloblastoma (MB) is the most common malignant brain tumor in children. Dissemination of MB cells into the cerebrospinal fluid (CSF) initiates metastasis within the central nervous system. By simulating CSF dynamics based on magnetic resonance imaging of MB patients, we discovered that FSS is elevated at the cervicomedullary junction. Strikingly, we found that MB-relevant FSS promotes metastasis along mouse spinal cords. Mechanistically, FSS induces metastatic cell behaviours, including weakened cell-substrate adhesion, increased motility, cell clustering, and plasma membrane localization of glucose transporter 1 (GLUT1) to enhance glucose uptake. FSS is perceived by mechanosensitive ion channel PIEZO2, which drives actomyosin contractility-dependent GLUT1 recruitment at the plasma membrane. Genetic targeting of PIEZO2 or pharmacologic inhibition of GLUT1 mitigates metastasis. Collectively, these findings define a targetable FSS-activated mechano-metastatic cascade for the treatment of MB metastasis.

A Potential Neurotoxic Mechanism: Bisphenol S-Induced Inhibition of Glucose Transporter 1 Leads to ATP Excitotoxicity in the Zebrafish Brain.

Many environmental pollutants have neurotoxic effects, but the initial molecular events involved in these effects are unclear. Here, zebrafish were exposed to the neurotoxicant bisphenol S (BPS, 1, 10, or 100 μg/L) from the embryonic stage to the larval stage to explore the ability of BPS to interfere with energy metabolism in the brain. BPS, which is similar to a glucose transporter 1 (GLUT1) inhibitor, inhibited GLUT1 function but increased mitochondrial activity in the brains of larval zebrafish. Interestingly, GLUT1 inhibitor treatment and BPS exposure did not reduce energy production in the brain; instead, they increased ATP production by inducing the preferential use of ketone bodies. Moreover, BPS promoted the protein expression of the purinergic 2X receptor but inhibited the purinergic 2Y-mediated phosphatidylinositol signaling pathway, indicating that excess ATP acts as a neurotransmitter to activate the purinergic 2X receptor under the BPS-induced restriction of GLUT1 function. BPS-induced inhibition of GLUT1 increased the number of neurons but promoted apoptosis by activating ATP-purinergic 2X receptors in the brain, causing ATP excitatory neurotoxicity. Our data reveal a potential neurotoxic mechanism induced by BPS that may represent a new adverse outcome pathway.

GLUT1 mediates bronchial epithelial E-cadherin disruption in TDI-induced steroid-insensitive asthma

Objective Down-regulation of bronchial epithelial E-cadherin is an important of feature of severe asthma, including steroid-insensitive asthma. Yet, the mechanisms involved in E-cadherin disruption are not fully understood. This study was aimed to investigate the role of glucose transporter 1 (GLUT1) in dysregulation of E-cadherin in toluene diisocyanate (TDI)-induced steroid-insensitive asthma. Methods A murine model of steroid-insensitive asthma was established by TDI sensitization and aerosol inhalation. Selective GLUT1 antagonists WZB117 and BAY876 were given to BALB/c mice after airway challenge. In vitro, primary human bronchial epithelial cells (HBECs) cultured in an airway-liquid interface (ALI) were exposed to TDI. Results TDI exposure markedly up-regulated GLUT1 in murine lungs and HBECs. Pharmacological inhibition of GLUT1 with BAY876 decreased airway hyperresponsiveness, neutrophil and eosinophil accumulation, as well as type 2 inflammation in vivo. Besides, the TDI-induced down-regulated expression of full-length E-cadherin was also partly recovered, accompanied by inhibited secretion of soluble E-cadherin (sE-cadherin). WZB117 also exhibited mild therapeutic effects, though not significant. In vitro, treatment with GLUT1 inhibitor relieved the TDI-induced disruption of E-cadherin in HBECs. Conclusions Taken together, our data demonstrated that GLUT1 modulates bronchial epithelial E-cadherin dysfunction production in TDI-induced steroid-insensitive asthma.

Deciphering Tumor Response: The Role of Fluoro-18-d-Glucose Uptake in Evaluating Targeted Therapies with Tyrosine Kinase Inhibitors.

Background/Objectives: The inhibitory effects of tyrosine kinase inhibitors (TKIs) on glucose uptake through their binding to human glucose transporter-1 (GLUT-1) have been well documented. Thus, our research aimed to explore the potential impact of various TKIs of GLUT-1 on the standard [18F]FDG-PET monitoring of tumor response in patients. Methods: To achieve this, we conducted an analysis on three patients who were undergoing treatment with different TKIs and harbored actionable alterations. Alongside the assessment of FDG data (including SUVmax, total lesion glycolysis (TLG), and metabolic tumor volume (MTV)), we also examined the changes in tumor sizes through follow-up [18F]FDG-PET/CT imaging. Notably, our patients harbored alterations in BRAFV600, RET, and c-KIT and exhibited positive responses to the targeted treatment. Results: Our analysis revealed that FDG data derived from SUVmax, TLG, and MTV offered quantifiable outcomes that were consistent with the measurements of tumor size. Conclusions: These findings lend support to the notion that the inhibition of GLUT-1, as a consequence of treatment efficacy, could be indirectly gauged through [18F] FDG-PET/CT imaging in cancer patients undergoing TKI therapy.

Mast Cells are Dependent on Glucose Transporter 1 (GLUT1) and GLUT3 for IgE-mediated Activation

Mast cells (MCs) are known to have a pathological impact in a variety of settings, in particular in allergic conditions. There is also limited evidence implicating MCs in diabetes, raising the possibility that MC function may be influenced by alterations in glucose levels. However, it is not known whether MCs are directly affected by elevated glucose concentrations. Moreover, it is not known which glucose transporters that are expressed by MCs, and whether MCs are dependent on glucose transporters for activation. Here we addressed these issues. We show that MCs express high levels of both glucose transporter 1 (GLUT1/Slc2A1) and GLUT3 (Slc2A3). Further, we show that the inhibition of either GLUT1 or GLUT3 dampens both MC degranulation and cytokine induction in response to IgE receptor crosslinking, and that combined GLUT1 and GLUT3 inhibition causes an even more pronounced inhibition of these parameters. In contrast, the inhibition of GLUT1 or GLUT3, or combined GLUT1 and GLUT3 inhibition, had less impact on the ability of the MCs to respond to activation via compound 48/80. Elevated glucose concentrations did not affect MC viability, and had no stimulatory effect on MC responses to either IgE receptor crosslinking or compound 48/80. Altogether, these findings reveal that MCs are strongly dependent on glucose transport via GLUT1 and/or GLUT3 for optimal responses towards IgE-mediated activation, whereas MC functionality is minimally affected by elevated glucose levels. Based on these findings, antagonists of GLUT1 and GLUT3 may be considered for therapeutic intervention in allergic conditions.

GLUT1 regulates the release of VEGF-A in the alveolar epithelium of lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is a severe disease with high mortality and poor prognosis, characterized by excessive and uncontrolled inflammatory response. Vascular endothelial growth factor A (VEGF-A) contributes to the development and progression of ALI. The aim of this study was to evaluate the role of glucose transporter 1 (GLUT1) in alveolar epithelial VEGF-A production in lipopolysaccharide (LPS)-induced ALI. An ALI mouse model was induced by LPS oropharyngeal instillation. Mice were challenged with LPS and then treated with WZB117, a specific antagonist of GLUT1. For the vitro experiments, cultured A549 cells (airway epithelial cell line) were exposed to LPS, with or without the GLUT1 inhibitors WZB117 or BAY876. LPS significantly upregulated of GLUT1 and VEGF-A both in the lung from ALI mice and in cultured A549. In vivo, treatment with WZB117 not only markedly decreased LPS-induced pulmonary edema, injury, neutrophilia, as well as levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF), but also reduced VEGF-A production. Yet, the maximum tolerated concentration of WZB117 failed to suppress LPS-induced VEGF-A overexpression in vitro. While administration of BAY876 inhibited gene and protein expression as well as secretion of VEGF-A in response to LPS in A549. These results illustrated that GLUT1 upregulates VEGF-A production in alveolar epithelia from LPS-induced ALI, and inhibition of GLUT1 alleviates ALI.

GLUT1 contributes to impaired epithelial tight junction in the late phase of acute lung injury

Dysfunction of epithelial barrier is crucial for the development of acute lung injury (ALI). This study was aimed to evaluate the role of glucose transporter 1 (GLUT1) in dysregulation of epithelial tight junction in ALI. GLUT1 was inhibited with specific antagonists WZB117 or BAY876 to see the effects on epithelial tight junction in a well-established LPS-induced mouse ALI model as well as in vitro cultured epithelial cells. Pharmacological inhibition of GLUT1 with WZB117 at either a low or high dose had no effects on lung injury and inflammation 24 h after LPS challenge, but significantly decreased the pulmonary inflammatory responses induced by LPS at 72 h with a high dose, which was verified by treatment with BAY876. WZB117 or BAY876 also recovered the expression of epithelial tight junction proteins ZO-1 and occludin. In cultured BEAS-2B and A549 cells, LPS induced increased GLUT1 expression, accompanied by decreased expression of tight junction protein ZO-1 and occludin. Blockade of GLUT1 restored LPS-induced disruption of ZO-1 and occludin in BEAS-2B rather than A549. Taken together, our results showed that GLUT1 is responsible for dysfunction of epithelial tight junctions in the late phase of LPS-induced ALI.

Iron promotes glycolysis to drive colon tumorigenesis

Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment. 13C-labeled glucose flux analysis indicated that the levels of several labeled glycolytic products were significantly increased, whereas several tricarboxylic acid cycle intermediates were significantly decreased in colonoids after iron treatment. Mechanistic studies showed that iron upregulated the expression of glucose transporter 1 (GLUT1) and mediated an inhibition of the pyruvate dehydrogenase (PDH) complex function via directly binding with tankyrase and/or pyruvate dehydrogenase kinase (PDHK) 3. Pharmacological inhibition of GLUT1 or PDHK reactivated PDH complex function and reduced high iron diet-enhanced tumor formation. In conclusion, excess iron promotes glycolysis and colon tumor growth at least partly through the inhibition of the PDH complex function.

Inhibitory effects of flavonoids on glucose transporter 1 (GLUT1): From library screening to biological evaluation to structure-activity relationship

Glucose transporter 1 (GLUT1) is mainly responsible for glucose uptake and energy metabolism, especially in the aerobic glycolysis process of tumor cells, which is closely associated with the advancement of tumors. Numerous studies have demonstrated that the inhibition of GLUT1 can decrease the growth of tumor cells and enhance drug sensitivity, so GLUT1 is considered to be a promising therapeutic target for cancer treatment. Flavonoids are a group of phenolic secondary metabolites present in vegetables, fruits, and herbal products, some of which were reported to increase cancer cells' sensitivity to sorafenib by inhibiting GLUT1. Our objective was to screen potential inhibitors of GLUT1 from 98 flavonoids and assess the sensitizing effect of sorafenib on cancer cells. and illuminate the structure–activity relationships of flavonoids with GLUT1. Eight flavonoids, including apigenin, kaempferol, eupatilin, luteolin, hispidulin, isosinensetin, sinensetin, and nobiletin exhibited significant inhibition (>50%) on GLUT1 in GLUT1-HEK293T cells. Among them, sinensetin and nobiletin showed stronger sensitizing effects and caused a sharp downward shift of the cell viability curves in HepG2 cells, illustrating these two flavonoids might become sensitizers to enhance the efficacy of sorafenib by inhibiting GLUT1. Molecular docking analysis elucidated inhibitory effect of flavonoids on GLUT1 was related to conventional hydrogen bonds, but not Pi interactions. The pharmacophore model clarified the critical pharmacophores of flavonoids inhibitors are hydrophobic groups in 3’positions and hydrogen bond acceptors. Thus, our findings would provide useful information for optimizing flavonoid structure to design novel GLUT1 inhibitors and overcome drug resistance in cancer treatment.

Pharmacophore-Based Virtual Screening Toward the Discovery of Novel GLUT1 Inhibitors

Glucose transporter 1 (GLUT1) plays an important role in the transport of glucose into cells. Studies found that GLUT1 is highly expressed in a variety of tumor cells, and it’s the rate-limiting transporter for tumor cells to uptake glucose, meaning that GLUT1 is a potential target for tumor treatment. Thus, the inhibition of GLUT1 by novel small compounds to lower glucose levels for cancer cells has become an emerging strategy. In this study, potential GLUT1 inhibitors were discovered by pharmacophore-based high-throughput virtual screening. First, 96 GLUT1 inhibitors were used to establish common pharmacophore hypotheses. The best pharmacophore model ADHRRR_1 was used to screen the ZINC database. Then, ADMET was launched to predict the pharmacokinetics of hit compounds from virtual screening. After that, the standard docking and precise docking were employed to dock these compounds with 4PYP protein; five molecules were selected as candidates of GLUT1 inhibitors for further analysis. Molecular Dynamic (MD) simulations and Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) method were applied to evaluate the binding stability and affinity of the five protein–ligand composites. Finally, Zinc000068152777 and Zinc000141918576 with lower docking scores and binding free energy emerged as the potential GLUT1 inhibitors. Taken together, these results in our study may provide valuable information for cancer therapeutics by disturbing the energy metabolism of tumors.

YAP: The nexus between metabolism and cardiac remodeling.

Cardiomyocyte hypertrophy is an integral part of cardiac remodeling that occurs under physiological or pathological stresses. It can lead to heart failure in a pathological form or oppose functional deterioration in a compensatory one. The mechanisms underlying an adaptive outcome of hypertrophy are ill defined. In this issue of the JCI, Kashihara et al. explored the role of the Yes-associated protein 1 (YAP) transcription factor in the heart, using cell culturing and mouse models. YAP activity was found to be associated with changes in genes of the glycolytic and auxiliary pathways under stress. Notably, YAP upregulated glucose transporter 1 (GLUT1), and inhibition of GLUT1 blocked YAP-induced hypertrophy but worsened heart function. These findings suggest that YAP is a regulator of metabolic reprogramming in the heart during compensatory hypertrophy. This insight may help in the development of future therapies for heart failure.

The GLUT1–mTORC1 axis affects odontogenic differentiation of human dental pulp stem cells

Human dental pulp stem cells (hDPSCs) are considered valuable for regenerative therapy. Although glucose transporter 1 (GLUT1) is known to play a critical role in cell differentiation, its mechanism of the odontogenic differentiation of hDPSCs remains unclear. This study was conducted to investigate the effect and underlying mechanisms of GLUT1 on odontogenic differentiation of hDPSCs. hDPSCs was treated with phloretin (Phl), a GLUT1 inhibitor. The impact of GLUT1 on the odontogenic differentiation of hDPSCs was analysed using quantitative real-time polymerase chain reaction, alizarin-red staining, and western blotting. Glucose uptake by hDPSCs was significantly inhibited by Phl treatment. Overall, inhibition of GLUT1 upregulated the expression of DSPP, DMP1, RUNX2, and OCN and increased the formation of mineralised nodules on odontogenic induction of hDPSCs. The levels of phosphorylated mTOR and ribosomal protein S6 kinase 1 (p70S6K) were increased after GLUT1 inhibition and decreased by an mTOR inhibitor (rapamycin, Rapa) during the odontogenic induction of hDPSCs. Moreover, mTOR suppression decreased the expression of the genes described above and formation of mineralised nodules. These results suggest that inhibition of GLUT1 promoted the odontogenic differentiation of hDPSCs via the mTORC1–p70S6K axis, providing a foundation for further application of hDPSCs in regenerative therapy.

Extracellular vesicle glucose transporter-1 and glycan features in monocyte-endothelial inflammatory interactions

Monocyte-induced endothelial cell inflammation is associated with multiple pathological conditions, and extracellular vesicles (EVs) are essential nanosized components of intercellular communication. EVs derived from endotoxin-stimulated monocytes were previously shown to carry pro-inflammatory proteins and RNAs. The role of glucose transporter-1 (GLUT-1) and glycan features in monocyte-derived EV-induced endothelial cell inflammation remains largely unexplored. This study demonstrates that EVs derived from endotoxin-stimulated monocytes activate inflammatory pathways in endothelial cells, which are partially attributed to GLUT-1. Alterations in glycan features and increased levels of GLUT-1 were observed in EVs derived from endotoxin-stimulated monocytes. Notably, inhibition of EV-associated GLUT-1, through the use of fasentin, suppressed EV-induced inflammatory cytokines in recipient endothelial cells.

Long noncoding RNA SLC2A1-AS1 regulates aerobic glycolysis and progression in hepatocellular carcinoma via inhibiting the STAT3/FOXM1/GLUT1 pathway.

Hepatocellular carcinoma (HCC) is one of the most lethal malignant diseases worldwide. Despite advances in the diagnosis and treatment of HCC, its overall prognosis remains poor. Recent studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in various pathophysiological processes, including liver cancer. In the current study, we report that lncRNA SLC2A1‐AS1 is frequently downregulated in HCC samples, as shown by quantitative real‐time polymerase chain reaction analysis. SLC2A1‐AS1 deletion is significantly associated with recurrence‐free survival in HCC. By performing glucose uptake, lactate production and ATP detection assays, we found that SLC2A1‐AS1‐mediated glucose transporter 1 (GLUT1) downregulation significantly suppressed glycolysis of HCC. In vitro Cell Counting Kit‐8, colony formation, transwell assays as well as in vivo tumorigenesis and metastasis assays showed that SLC2A1‐AS1 overexpression significantly suppressed proliferation and metastasis in HCC through the transcriptional inhibition of GLUT1. Results from fluorescence in situ hybridization, ChIP and luciferase reporter assays demonstrated that SLC2A1‐AS1 exerts its regulatory role on GLUT1 by competitively binding to transketolase and signal transducer and activator of transcription 3 (STAT3) and inhibits the transactivation of Forkhead box M1 (FOXM1) via STAT3, thus resulting in inactivation of the FOXM1/GLUT1 axis in HCC cells. Our findings will be helpful for understanding the function and mechanism of lncRNA in HCC. These data also highlight the crucial role of SLC2A1‐AS1 in HCC aerobic glycolysis and progression and pave the way for further research regarding the potential of SLC2A1‐AS1 as a valuable predictive biomarker for HCC recurrence.

Glucose transporter 1 in rheumatoid arthritis and autoimmunity.

Knowledge about metabolism of immune cells increased almost exponentially during the last two decades and thereby created the new area immunometabolism. Increased glucose uptake and glycolysis were identified as one of the major drivers in immune cells for rapid adaptation to changes in the microenvironment or external stimuli. These metabolic switches are crucial to generate macromolecules for immune cell proliferation and activation. Glucose transporter 1 (GLUT1), a ubiquitously expressed glucose transporter, is strongly upregulated after innate and adaptive immune cell activation. Deletion or inhibition of GLUT1 blocked T cell proliferation and effector function, antibody production from B cells and reduced inflammatory responses in macrophages. Increased glucose uptake and GLUT1 expression are not only observed in proinflammatory conditions, but also in murine models of autoimmunity as well as in human patients. Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by infiltration of immune cells, hyperproliferation of fibroblast-like synoviocytes, and destruction of cartilage and bone. These processes create a hypoxic microenvironment in the synovium. Moreover, synovial samples including fibroblast-like synoviocytes from RA patients showed increased lactate level and upregulate GLUT1. Similar upregulation of GLUT1 is observed in systemic lupus erythematosus and psoriasis patients as well as in murine autoimmune models. Inhibition of GLUT1 using either T cell specific knockouts or small molecule GLUT1/glycolysis inhibitors improved phenotypes of different murine autoimmune disease models like arthritis, lupus, and psoriasis. Thereby the therapeutic potential of immunometabolism and especially interference with glycolysis was proven. This article is categorized under: Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Translational Medicine Physiology > Mammalian Physiology in Health and Disease.

SODD promotes glucose uptake of colorectal cancer cells via AKT pathway.

Altered glucose metabolism has been found in a variety of malignant diseases and recognized as one of the hallmarks of cancer. However, the molecular mechanism behind it is far from well understood. In current study, we found silencer of death domains (SODD) regulates glucose uptake of colorectal cancer cells. When cultured under low level of glucose, SODD overexpressing RKO and SW1417 cells generated more colonies, compared with control cells, in clonogenic assay. SODD upregulation enhanced RKO and SW1417 cells viability. Furthermore, SODD induced more GLUT1 (Glucose transporter 1) expression and enhanced glucose uptake. AKT phosphorylation was upregulated in SODD overexpression cells. Moreover, inhibition of GLUT1 or AKT could reverse SODD induced glucose uptake enhancement. In conclusion, our findings indicate that SODD positively regulates glucose uptake and may be a potential therapeutic target of colorectal cancer.

GLUT-1 siRNA Enhances Radiosensitization Of Laryngeal Cancer Stem Cells Via Enhanced DNA Damage, Cell Cycle Redistribution, And Promotion Of Apoptosis In Vitro And In Vivo.

BackgroundRadiotherapy does not show good efficacy against laryngeal cancer due to radioresistance. Cancer stem cells (CSCs) are considered among the causes of radioresistance. Inhibition of glucose transporter-1 (GLUT-1) using GLUT-1 small interfering RNA (siRNA) may enhance the radiosensitivity of laryngeal cancer cells, but the underlying cellular mechanisms remain unclear.MethodsThe CD133+-Hep-2R cell line was established with repeated irradiation and magnetic-activated cell sorting. The effects of irradiation on CD133+-Hep-2R cells were examined by CCK-8 assay, Transwell assay, quantitative real-time polymerase chain reaction (RT-PCR), and Western blotting. The effects of GLUT-1 siRNA on the radiosensitivity of CD133+-Hep-2/2R cells were examined by RT-PCR, Western blotting, CCK-8 assay, colony formation assay, and Transwell assay in vitro and in a xenograft tumor model in nude mice. The cellular mechanism of enhanced radiosensitivity associated with GLUT-1 siRNA was investigated. The cell cycle and apoptosis rate were analyzed by flow cytometry, and the repair capability was examined by determining the levels of RAD51 and DNA-PKcs.ResultsCD133+-Hep-2/2R cells showed stronger proliferation, lower apoptosis rate, lower percentage of G0/G1 phase cells, higher percentages of S and G2/M phase cells, and higher expression levels of GLUT-1 than Hep-2/2R cells. Transfection with GLUT-1 siRNA inhibited the proliferation and invasive capability of CD133+-Hep-2R cells by inhibiting GLUT-1 expression, which also caused a redistribution of the cell cycle (higher proportion of cells in the G0/G1 phase and lower proportion in the S and G2/M phases), increased the apoptosis rate, and reduced DNA repair capability by suppressing RAD51 and DNA-PKcs expression.ConclusionThe results of this study suggest that GLUT-1 siRNA can enhance the radiosensitivity of CD133+-Hep-2R cells by inducing a redistribution of cell cycle phases, inhibiting DNA repair capability, and increasing apoptosis. Inhibition of GLUT-1 may have therapeutic potential for interventions to increase the radiosensitivity of laryngeal CSCs.

ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer.

SummaryUterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer.

Glucose transporter 1 (GLUT1) expression is a prognostic marker for esophageal squamous cell carcinoma (ESCC). Recent work on GLUT1 and development of specific inhibitors supports the feasibility of GLUT1 inhibition as a treatment for various cancers. The anti–proliferative effects of GLUT1‐specific small interfering RNA (siRNA) and a GLUT1 inhibitor were evaluated in ESCC cell lines. Expression of pro–proliferative and anti–proliferative signaling and effector molecules was examined by western blotting and quantitative RT‐PCR. GLUT1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy. The reduction in standardized uptake value (SUV) of 18F‐fluoro‐deoxyglucose was calculated using the formula: ([pretreatment SUV max – posttreatment SUV max]/pretreatment SUV max) × 100. GLUT1‐specific siRNA expression in ESCC cells inhibited their proliferation, increased expression of p27kip, and decreased expression of cyclin‐dependent kinase 6, pyruvate kinase muscle isozyme M2, lactate dehydrogenase A and phospho‐ERK1/2. Suppression of GLUT1 by siRNA increased low‐dose cisplatin‐induced inhibition of proliferation of TE‐11 ESCC cells, which express high GLUT1 levels. Similarly, BAY‐876, a GLUT1 inhibitor, enhanced cisplatin‐mediated inhibition of ESCC cell proliferation. GLUT1 expression in pretreatment biopsy samples was associated with the response to chemotherapy as well as the pathological tumor stage and histological response grade after esophagectomy. Finally, GLUT1‐negative tumors showed a significantly larger reduction in SUV max (61.2% ± 4.5%) compared with GLUT1‐positive tumors (46.2% ± 4.4%). GLUT1 expression may be a surrogate marker of response to chemotherapy, and inhibition of GLUT1 may be a potential novel therapy for ESCC patients.

Ovarian Cancer Relies on Glucose Transporter 1 to Fuel Glycolysis and Growth: Anti-Tumor Activity of BAY-876.

The recent progresses in understanding of cancer glycolytic phenotype have offered new strategies to manage ovarian cancer and other malignancies. However, therapeutic targeting of glycolysis to treat cancer remains unsuccessful due to complex mechanisms of tumor glycolysis and the lack of selective, potent and safe glycolytic inhibitors. Recently, BAY-876 was identified as a new-generation inhibitor of glucose transporter 1 (GLUT1), a GLUT isoform commonly overexpressed but functionally poorly defined in ovarian cancer. Notably, BAY-876 has not been evaluated in any cell or preclinical animal models since its discovery. We herein took advantage of BAY-876 and molecular approaches to study GLUT1 regulation, targetability, and functional relevance to cancer glycolysis. The anti-tumor activity of BAY-876 was evaluated with ovarian cancer cell line- and patient-derived xenograft (PDX) models. Our results show that inhibition of GLUT1 is sufficient to block basal and stress-regulated glycolysis, and anchorage-dependent and independent growth of ovarian cancer cells. BAY-876 dramatically inhibits tumorigenicity of both cell line-derived xenografts and PDXs. These studies provide direct evidence that GLUT1 is causally linked to the glycolytic phenotype in ovarian cancer. BAY-876 is a potent blocker of GLUT1 activity, glycolytic metabolism and ovarian cancer growth, holding promise as a novel glycolysis-targeted anti-cancer agent.