MCT4 Promotes Tumor Malignancy in F98 Glioma Cells

Reuss, Anna Maria; Groos, Dominik; Ghoochani, Ali; Buchfelder, Michael; Savaskan, Nicolai Ε.

doi:10.1155/2021/6655529

Cited by 9 publications

(19 citation statements)

References 60 publications

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“…This mechanism enhances the glucose gradient, ensuring energy delivery into hypoxic tumor regions, and therefore, the overall survival of the tumor. This model is consistent with findings that MCT4 is upregulated in the perinecrotic core of GBM, whereas MCT1 is mainly overexpressed at the leading edge [ 43 , 44 ]. Furthermore, it has been shown that under glucose deprivation, lactate preserves high ATP levels in glioma cells [ 44 ], sustaining the high-energy demands of proliferating tumor cells.…”

Section: Lactic Acid Metabolism Within the Tumor Microenvironmentsupporting

confidence: 92%

“…Indeed, the extracellular pH of most tumors has been determined to be much lower than in normal tissues [50]. For instance, electrode measurements of pH in human brain tumors have revealed a minimum of 5.9 and a mean of 6.8 compared [41][42][43]. This overexpression is associated with poorer overall survival of GBM patients.…”

Section: An Acidic Tumor Microenvironment and The Metabolic Symbiosis Modelmentioning

confidence: 99%

“…MCT1 (SLC16A1) and MCT4 (SLC16A3) are overexpressed in patients with GBM compared to non-neoplastic control tissue and WHO grade 3 anaplastic and WHO grade 2 diffuse astrocytoma [ 41 , 42 , 43 ]. This overexpression is associated with poorer overall survival of GBM patients.…”

Section: Lactic Acid Metabolism Within the Tumor Microenvironmentmentioning

confidence: 99%

“…Interestingly, MCT1 is highly expressed at the leading tumor edge together with the Na + /H + exchanger (NHE )1 , whereas MCT4 is upregulated in the perinecrotic tumor center together with HIF-1α, LDH , and CA IX in GBM patients and in a rat glioma model [ 43 , 44 , 45 ]. Consistent with this finding, MCT4 expression is induced under hypoxic conditions in glioma cells, leading to enhanced lactic acid export and thereby decreased extracellular pH [ 43 , 46 ]. Accordingly, MCT4 transcription is activated by HIF-1α, binding to two HREs within the MCT4 promotor [ 47 ].…”

Section: Lactic Acid Metabolism Within the Tumor Microenvironmentmentioning

confidence: 99%

“…Likewise, lactate serum and tumor tissue levels are associated with malignancy grade in glioma [ 29 , 59 ]. Functional studies in glioma cells and GBM neurospheres have shown that MCT4 increases tumor cell proliferation and survival, whereas MCT4 knockdown or pharmacological inhibition leads to apoptosis and necrosis [ 43 , 60 ]. Furthermore, MCT4 enhances migration and invasiveness by reorganization of the actin cytoskeleton [ 43 ].…”

Section: Lactic Acid Metabolism Within the Tumor Microenvironmentmentioning

confidence: 99%

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The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

Reuss

Groos

Buchfelder

et al. 2021

IJMS

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Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between isocitrate dehydrogenase (IDH) mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.

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Section: Lactic Acid Metabolism Within the Tumor Microenvironmentsupporting

confidence: 92%

Section: An Acidic Tumor Microenvironment and The Metabolic Symbiosis Modelmentioning

confidence: 99%

Section: Lactic Acid Metabolism Within the Tumor Microenvironmentmentioning

confidence: 99%

Section: Lactic Acid Metabolism Within the Tumor Microenvironmentmentioning

confidence: 99%

Section: Lactic Acid Metabolism Within the Tumor Microenvironmentmentioning

confidence: 99%

See 3 more Smart Citations

The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

Reuss

Groos

Buchfelder

et al. 2021

IJMS

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Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma

Zhu

Gong

et al. 2022

Cancer Innovation

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Background Hypoxic microenvironment is immunosuppressive and protumorigenic, and elevated lactate is an intermediary in the modulation of immune responses. However, as critical lactate transporters, the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated. Methods Gene expression in low‐ and high‐grade glioma (LGG and GBM) was evaluated with TCGA database. The TISIDB, TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints. Results Compared with normal tissues, a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM, and closely related to the poor prognosis only in LGG. Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflammation in glioma. The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis. TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells, which was correlated to tumor‐associated macrophages and neutrophils that are immunosuppressive. SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints (especially PD1, PD‐L1, PD‐L2, Tim‐3) and immunosuppressive factors (TGF‐β and IL‐10) in glioma. Furthermore, SLC16A3 had a positive correlation to activation markers of tumor‐associated neutrophils and chemokines such as CCL2, CCL22, CXCR2, CXCR4 in LGG and CCL7, CCL20 CXCL8 in GBM, which could enhance infiltration of immunosuppressive cells to the tumor microenvironment. Conclusion In general, our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immunosuppressive cell infiltration, which contributes to immune evasion and a worse prognosis in glioma. Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.

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LINC00035 Transcriptional Regulation of SLC16A3 via CEBPB Affects Glycolysis and Cell Apoptosis in Ovarian Cancer

Yang

Wang

Cheng

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Objective. Ovarian cancer (OC) represents the most lethal gynecologic malignancy globally. Over the decades, lncRNAs have been considered as study focuses due to their genome-wide expression through multiple mechanisms in which regulation of target gene transcription through interaction with transcription factors or epigenetic proteins is proven. In the present work, we focus on the functional role of LINC00035 in OC and its regulation mechanism on gene expression. Methods. We collected OC tissues and adjacent tumor-free tissues surgically resected from 67 OC patients. Cultured human OC cell lines SKOV3 and A2780 were assayed for their viability, migration, invasion, apoptosis in vitro using CCK-8 assays, transwell assays, and flow cytometric analysis. OC cell tumorigenesis in vivo was evaluated by mouse xenograft experiments. Glycolysis was evaluated by glucose uptake, lactate release, and ATP production assays. Luciferase activity assay, RNA immunoprecipitation (RIP), and RNA pull-down were performed to confirm the interactions among LINC00035, CEBPB, and SLC16A3. Results. LINC00035 was upregulated in OC tissues. LINC00035 knockdown was shown to repress SKOV3 and A2780 cell viability, migration, invasion, induce their apoptosis, and reduce glucose uptake, lactate release, and ATP production. LINC00035 could recruit CEBPB into the SLC16A3 promoter region, thus increasing the SLC16A3 transcription. SLC16A3 was upregulated in OC tissues. SLC16A3 knockdown exerted similar effects on SKOV3 and A2780 cells as LINC00035 knockdown. Rescue experiments found SLC16A3 overexpression resisting to LINC00035 knockdown on SKOV3 and A2780 cell viability, migration, invasion, apoptosis, glucose uptake, lactate release, and ATP production. Results also showed LINC00035 knockdown could inhibit OC cell tumorigenesis in vivo. Conclusion. The study reveals that LINC00035 promotes OC progression by regulating glycolysis and cell apoptosis through CEBPB-mediated transcriptional promotion of SLC16A3.

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MCT4 Promotes Tumor Malignancy in F98 Glioma Cells

Cited by 9 publications

References 60 publications

The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma

LINC00035 Transcriptional Regulation of SLC16A3 via CEBPB Affects Glycolysis and Cell Apoptosis in Ovarian Cancer

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