MCT4 Promotes Tumor Malignancy in F98 Glioma Cells

Anna Maria Reuss,Michael Buchfelder,Ali Ghoochani,Nicolai Savaskan,Dominik Groos,Dali Zheng

doi:10.1155/2021/6655529

Anna Maria Reuss, Michael Buchfelder + Show 4 more

Open Access

https://doi.org/10.1155/2021/6655529

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Abstract

Monocarboxylate transporter 4 (MCT4, SLC16A3) is elevated under hypoxic conditions in many malignant tumors including gliomas. Moreover, MCT4 expression is associated with shorter overall survival. However, the functional consequences of MCT4 expression on the distinct hallmarks of cancer have not yet been explored at the cellular level. Here, we investigated the impact of MCT4 overexpression on proliferation, survival, cell death, migration, invasion, and angiogenesis in F98 glioma cells. Stable F98 glioma cell lines with MCT4 overexpression, normal expression, and knockdown were generated. Distinct hallmarks of cancer were examined using in silico analysis, various in vitro cell culture assays, and ex vivo organotypic rat brain slice culture model. Consistent with its function as lactate and proton exporter, MCT4 expression levels correlated inversely with extracellular pH and proportionally with extracellular lactate concentrations. Our results further indicate that MCT4 promotes proliferation and survival by altered cell cycle regulation and cell death mechanisms. Moreover, MCT4 overexpression enhances cell migration and invasiveness via reorganization of the actin cytoskeleton. Finally, MCT4 inhibition mitigates the induction of angiogenesis, suggesting that MCT4 also plays a crucial role in tumor-related angiogenesis. In summary, our data highlight MCT4/SLC16A3 as a key gene for distinct hallmarks of tumor malignancy in glioma cells.

Highlights

Malignant gliomas are the most common primary malignant brain tumors with an increasing incidence of up to nine per 100,000 habitants over the last years [1, 2]. is brain tumor type is highly proliferative and shows an infiltrative growth pattern, accounting for the high recurrence rates in patients
We investigated the impact on tumor malignancy in F98 glioma cells using in silico analysis, in vitro cell culture assays, and ex vivo vascular organotypic glioma impact model (VOGIM) [35] by implanting F98 cells into rat brain slices
We have shown that MCT4 expression has functional effects. erefore, this model has allowed us to study the functional consequences of MCT4 expression in F98 glioma cells

Summary

Introduction

Malignant gliomas are the most common primary malignant brain tumors with an increasing incidence of up to nine per 100,000 habitants over the last years [1, 2]. is brain tumor type is highly proliferative and shows an infiltrative growth pattern, accounting for the high recurrence rates in patients. In the metabolic symbiosis model, these cells have been proposed to overexpress MCT4 to release high amounts of lactate produced during anaerobic glycolysis into the tumor microenvironment. In line with this observation, elevated extracellular lactate concentrations up to 40 mM and corresponding low extracellular pH (pHe) have been found in solid tumors under hypoxic conditions [18,19,20,21,22]. Upregulated MCT4 has been linked to altered tumor metabolism as well as to increased growth and survival in breast and pancreatic cancer [33, 34]. There has only been one previous functional study investigating MCT4 in glioblastoma (GBM) neurospheres, mainly focusing on tumor growth and survival dependent on the oxygen level [14]

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