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PLoS One. 2017 Apr 20;12(4):e0176162. doi: 10.1371/journal.pone.0176162. eCollection 2017.

Metabolic analysis of radioresistant medulloblastoma stem-like clones and potential therapeutic targets.

Author information

1
Department of Radiological Health Science, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan.
2
Department of Radiobiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
3
Proton Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
4
Central Institute of Isotope Science, Hokkaido University, Sapporo, Hokkaido, Japan.
5
Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
6
Center for Integrative Medicine, Tsukuba University of Technology, Tsukuba, Ibaraki, Japan.
7
Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

Abstract

Medulloblastoma is a fatal brain tumor in children, primarily due to the presence of treatment-resistant medulloblastoma stem cells. The energy metabolic pathway is a potential target of cancer therapy because it is often different between cancer cells and normal cells. However, the metabolic properties of medulloblastoma stem cells, and whether specific metabolic pathways are essential for sustaining their stem cell-like phenotype and radioresistance, remain unclear. We have established radioresistant medulloblastoma stem-like clones (rMSLCs) by irradiation of the human medulloblastoma cell line ONS-76. Here, we assessed reactive oxygen species (ROS) production, mitochondria function, oxygen consumption rate (OCR), energy state, and metabolites of glycolysis and tricarboxylic acid cycle in rMSLCs and parental cells. rMSLCs showed higher lactate production and lower oxygen consumption rate than parental cells. Additionally, rMSLCs had low mitochondria mass, low endogenous ROS production, and existed in a low-energy state. Treatment with the metabolic modifier dichloroacetate (DCA) resulted in mitochondria dysfunction, glycolysis inhibition, elongated mitochondria morphology, and increased ROS production. DCA also increased radiosensitivity by suppression of the DNA repair capacity through nuclear oxidization and accelerated the generation of acetyl CoA to compensate for the lack of ATP. Moreover, treatment with DCA decreased cancer stem cell-like characters (e.g., CD133 positivity and sphere-forming ability) in rMSLCs. Together, our findings provide insights into the specific metabolism of rMSLCs and illuminate potential metabolic targets that might be exploited for therapeutic benefit in medulloblastoma.

PMID:
28426747
PMCID:
PMC5398704
DOI:
10.1371/journal.pone.0176162
[Indexed for MEDLINE]
Free PMC Article

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