Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

Miranda-Gonçalves, Vera; Granja, Sara; Martinho, Olga; Honavar, Mrinalini; Pojo, Marta; Costa, Bruno M.; Pires, Manuel Melo; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Reis, Rui Manuel; Baltazar, Fátima

doi:10.18632/oncotarget.10114

Cited by 86 publications

(81 citation statements)

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“…Although only a small number of studies have investigated the role of MCT expression in brain tumors, the studies universally support the importance of MCTs, particularly MCT1 in these tumors . Our group reported that MCT1 is the most prevalent MCT isoform expressed in the plasma membrane of GBM cells and that its expression is upregulated in regions of hypoxia . Despite the fact that another MCT isoform, MCT4, is better adapted to support cancer glycolytic metabolism, MCT1 has been demonstrated to play an important role in tumor cell growth and aggressiveness, as well as in mediating lactate efflux to the tumor microenvironment .…”

Section: Introductionmentioning

confidence: 80%

“…The cells were then incubated for 24 h in CM or serum‐free DMEM media. IF staining was performed as previously described . The secondary antibodies used were goat anti‐rabbit‐Alexa Fluor 488 (1:500; A11008, Invitrogen) for MCT4, MCT1, and GLUT‐1 and goat anti‐mouse‐Alexa Fluor 594 (1:250; A11032, Invitrogen) for CD147.…”

Section: Methodsmentioning

confidence: 99%

“…WB was performed as described previously to detect levels of MCT1, MCT4, GLUT1, and CD147. Incubation with primary antibodies was performed overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were plated in 48‐well plates at a density of 3 × 10 4 cells per well and allowed to adhere overnight. After incubating the cells for 24 h in CM or serum‐free DMEM media, the lactate content of the cell culture medium was quantified using a commercial enzymatic colorimetric kit (Spinreact, Bioquimica, Spain) . Total protein (expressed as total biomass) of the cells was then measured using the sulforhodamine B assay (SRB, TOX‐6, Sigma‐Aldrich).…”

Section: Methodsmentioning

confidence: 99%

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Monocarboxylate transporter 1 is a key player in glioma‐endothelial cell crosstalk

Miranda-Gonçalves

Bezerra

Costa‐Almeida

et al. 2017

Molecular Carcinogenesis

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Glioblastoma (GBM) is one of the most glycolytic and angiogenic human tumors, characteristics that contribute to the poor prognosis associated with this type of tumor. A lactate shuttle has been described between tumor cells and endothelial cells (ECs), with the monocarboxylate transporters (MCTs) acting as important players in this tumor-EC communication. In this study, we aimed to understand how the tumor microenvironment modulates EC metabolism, and to characterize the role of MCTs in the glioma-brain EC crosstalk. Exposure of human brain microvascular ECs (HBMEC) to GBM cell-conditioned media increased the expression of MCT1, which corresponded to activation of oxidative metabolism and an increase in angiogenic capacity, as determined by increased proliferation, migration, and vessel assembly. Lactate depletion from the microenvironment or inhibition of lactate uptake in HBMEC induced an increase in lactate production and a decrease in proliferation, migration, and vessel assembly. Moreover, addition of lactate to HBMEC media promoted activation of AKT and AMPK pathways and increased expression in NFκB, HIF-1α, and the lactate receptor GPR81. Here, we demonstrate a role for MCT1 as a mediator of lactate signaling between glioma cells and brain ECs. Our results suggest that MCT1 can mediate EC metabolic reprograming, proliferation, and vessel sprouting in response to tumor signaling. Thus, targeting MCT1 in both tumor cells and brain EC may be a promising therapeutic strategy for the treatment of GBM.

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Section: Introductionmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

“…WB was performed as described previously to detect levels of MCT1, MCT4, GLUT1, and CD147. Incubation with primary antibodies was performed overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Monocarboxylate transporter 1 is a key player in glioma‐endothelial cell crosstalk

Miranda-Gonçalves

Bezerra

Costa‐Almeida

et al. 2017

Molecular Carcinogenesis

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“…This process is known as anaerobic glycolysis and has been extensively studied throughout the years, but is still poorly understood [6,7]. Recent studies demonstrated that tumor cells prefer the anaerobic metabolism because it more efficiently produces energy and basic metabolites for protein biosynthesis as compared to aerobic metabolism [8,9]. These findings were confirmed in a study showing that one of the main molecule that control glycolysis and the anaerobic metabolism, the glucosetransporter (GLUT), was up regulated in breast tumor cell lines [10].…”

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confidence: 99%

Metabolism: A New Frontier in Cancer Research

Rodrigues¹

2017

JCPCR

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Submit Manuscript | http://medcraveonline.com development and can be used by the pharmaceutical industry to generate novel drugs. This is validated by the approval of Agas and Celgene's enasidenib by the FDA. This drug modulates the metabolism and is used as a medication against acute myelogenous leukemia. Enasidenib is an inhibitor of the mutated isocitrate dehydrogenase (IDH2), one of the main enzymes of the citric acid cycle (also known as Krebs cycle), a central pathway which converts molecules coming from all 3 main catabolic pathways into intermediate metabolites that finally fuel the respiratory chain, the main energy providing process in cells. IDH enzymes usually metabolize isocitrate into α-ketoglutarate, a crucial step in the citric cycle. When mutated in some cancers, this enzyme starts producing 2-hydroxyglutarate, a metabolite that causes cell differentiation defects and impairs histone demethylation [3]. While this approval highlights the promising role of anticancer drugs modulating metabolism, researchers have struggled to find other therapeutically useful targets in metabolic pathways. Tumor MetabolismCell metabolism as well as cancer development and growth is complex. The intermodulation between metabolic pathways and the plasticity of these routes, plus the capacity of tumor cells to adapt are factors that slow down the advances in their understanding. Factors such as poor oxygenation, acidity and deprivation of nutrients, which normally cause cell death, are rapidly converted into promoters by tumor cells [4,5].The reprogramming of the glucose metabolism is a good example for this flexibility. Tumor cells typically exhibit a high uptake of glucose and are mainly metabolizing anaerobically. For many years, the explanation for that was attributed to the lack of oxygen, once the proliferation rate of tumor exceeds the angiogenesis. However, Otto Warburg (1927) verified that even in the presence of oxygen, tumor cells prefer to metabolize glucose into lactic acid. This process is known as anaerobic glycolysis and has been extensively studied throughout the years, but is still poorly understood [6,7]. Recent studies demonstrated that tumor cells prefer the anaerobic metabolism because it more efficiently produces energy and basic metabolites for protein biosynthesis as compared to aerobic metabolism [8,9]. These findings were confirmed in a study showing that one of the main molecule that control glycolysis and the anaerobic metabolism, the glucosetransporter (GLUT), was up regulated in breast tumor cell lines [10].To corroborate the complexity of cancer metabolism, it has been shown recently that some tumors also use the mitochondrial oxidative phosphorylations [11,12]. Growing evidence of the importance of the glucose metabolism for tumor development and the need of new therapeutic targets, lead to the application of drugs inhibiting the glycolytic pathway as potential approach. Metformin for example, a drug already widely used in diabetes treatment, decreases glucose consumption and, conseque...

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Combination Therapy With CD147‐Targeted Nanoparticles Carrying Phenformin Decreases Lung Cancer Growth

et al. 2023

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Lung cancer is one of the most fatal cancers worldwide. Resistance to conventional therapies remains a hindrance to patient treatment. Therefore, the development of more effective anti-cancer therapeutic strategies is imperative. Solid tumors exhibit a hyperglycolytic phenotype, leading to enhanced lactate production; and, consequently, its extrusion to the tumor microenvironment. Previous data reveals that inhibition of CD147, the chaperone of lactate transporters (MCTs), decreases lactate export in lung cancer cells and sensitizes them to phenformin, leading to a drastic decrease in cell growth. In this study, the development of anti-CD147 targeted liposomes (LUVs) carrying phenformin is envisioned, and their efficacy is evaluated to eliminate lung cancer cells. Herein, the therapeutic effect of free phenformin and anti-CD147 antibody, as well as the efficacy of anti-CD147 LUVs carrying phenformin on A549, H292, and PC-9 cell growth, metabolism, and invasion, are evaluated. Data reveals that phenformin decreases 2D and 3D-cancer cell growth and that the anti-CD147 antibody reduces cell invasion. Importantly, anti-CD147 LUVs carrying phenformin are internalized by cancer cells and impaired lung cancer cell growth in vitro and in vivo. Overall, these results provide evidence for the effectiveness of anti-CD147 LUVs carrying phenformin in compromising lung cancer cell aggressiveness.

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Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

Cited by 86 publications

References 53 publications

Monocarboxylate transporter 1 is a key player in glioma‐endothelial cell crosstalk

Monocarboxylate transporter 1 is a key player in glioma‐endothelial cell crosstalk

Metabolism: A New Frontier in Cancer Research

Combination Therapy With CD147‐Targeted Nanoparticles Carrying Phenformin Decreases Lung Cancer Growth

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