Catalase Overexpression Drives an Aggressive Phenotype in Glioblastoma.

Susanne Flor,Corinne E Griguer,Jeremy D Greenlee,Md Yousuf Ali,Kristen L Coleman,Claudia R Oliva,Varun Monga,Karra A Jones

doi:10.3390/antiox10121988

Abstract

Glioblastoma remains the deadliest form of brain cancer, largely because these tumors become resistant to standard of care treatment with radiation and chemotherapy. Intracellular production of reactive oxygen species (ROS) is necessary for chemo- and radiotherapy-induced cytotoxicity. Here, we assessed whether antioxidant catalase (CAT) affects glioma cell sensitivity to temozolomide and radiation. Using The Cancer Genome Atlas database, we found that CAT mRNA expression is upregulated in glioma tumor tissue compared with non-tumor tissue, and the level of expression negatively correlates with the overall survival of patients with high-grade glioma. In U251 glioma cells, CAT overexpression substantially decreased the basal level of hydrogen peroxide, enhanced anchorage-independent cell growth, and facilitated resistance to the chemotherapeutic drug temozolomide and ionizing radiation. Importantly, pharmacological inhibition of CAT activity reduced the proliferation of glioma cells isolated from patient biopsy samples. Moreover, U251 cells overexpressing CAT formed neurospheres in neurobasal medium, whereas control cells did not, suggesting that the radio- and chemoresistance conferred by CAT may be due in part to the enrichment of glioma stem cell populations. Finally, CAT overexpression significantly decreased survival in an orthotopic mouse model of glioma. These results demonstrate that CAT regulates chemo- and radioresistance in human glioma.

Highlights

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a mean survival of only 14 months [1], even with the current standard of care treatment, which includes temozolomide (TMZ) combined with radiotherapy [2,3]
Many factors have been associated with GBM resistance to radiation and chemotherapy, including tumor hypoxia, efficient and redundant DNA repair capacities [6], glioma stem cells (GSCs) [7], and increased expression of antioxidant enzymes that reduce the accumulation of reactive oxygen species (ROS) [8,9]
To investigate if CAT expression is clinically relevant in gliomas, we interrogated The Cancer Genome Atlas (TCGA) data accessed via GlioVis [37]

Summary

Introduction

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a mean survival of only 14 months [1], even with the current standard of care treatment, which includes temozolomide (TMZ) combined with radiotherapy [2,3]. Resistance to radio-chemotherapy presents the most challenging barrier in the successful treatment of cancer and is one of the main phenomena underlying the failure to achieve a sustainable clinical benefit for patients with GBM [4,5]. Many factors have been associated with GBM resistance to radiation and chemotherapy, including tumor hypoxia, efficient and redundant DNA repair capacities [6], glioma stem cells (GSCs) [7], and increased expression of antioxidant enzymes that reduce the accumulation of reactive oxygen species (ROS) [8,9]. Excess cellular levels of ROS cause damage to important macromolecules, such as DNA, proteins, and lipids [12], which can lead to the activation of cell death signaling pathways [13,14]. Intracellular ROS levels are controlled by a complex network of antioxidant enzymes (e.g., superoxide dismutase and glutathione peroxidase) [15]

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Results

Conclusion