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

Lue Sun,Hidehiko Nakagawa,Kazuya Ito,Hironobu Yasui,Osamu Inanami,Aki Hirayama,Koji Tsuboi,Yoshitaka Matsumoto,Takashi Moritake

doi:10.1371/journal.pone.0176162

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.

Highlights

Brain tumors are the leading cause of cancer-related death in children, responsible for 7 per 106 deaths in the USA and approximately 10 per 106 deaths in Japan; medulloblastoma is the most common malignant pediatric brain tumor, accounting for 20% of pediatric brain tumors in the USA and 12% in Japan [1,2,3,4]
Our findings indicate that cancer stem-like cells (CSLCs) metabolism plays an important role in maintaining cancer stem cell-like phenotypes and radioresistance, and provide greater insight into the development of metabolic targeting radiotherapy to disrupt medulloblastoma CSLCs
Tumorigenic cell frequencies calculated using the formula available on the WEHI ELDA website [43] for ONS-76, -F8, and -B11 were 1 in 4,747, 1 in 1,351 and 1 in 1,508, respectively (S1 Fig). These results showed that ONS-F8 and -B11 had higher tumorigenic ability than the parental ONS-76 cells

Summary

Introduction

Brain tumors are the leading cause of cancer-related death in children, responsible for 7 per 106 deaths in the USA and approximately 10 per 106 deaths in Japan; medulloblastoma is the most common malignant pediatric brain tumor, accounting for 20% of pediatric brain tumors in the USA and 12% in Japan [1,2,3,4]. Overall survival rates for medulloblastoma patients have improved in recent years the morbidity rate remains significant, with survivors often suffering from adverse neurologic, endocrinologic, and social effects with the current treatment options [5,6,7,8,9,10]. There is an urgent need to better understand the mechanism of therapy refractoriness and to develop novel and specific tumor therapies with reduced brain toxicity for medulloblastoma patients. Recent molecular-based classifications divide medulloblastomas into four subtypes to allow more accurate patient stratification and an appropriate clinical approach for each patient [9, 11]. Understanding medulloblastoma CSLCs in more depth will aid development of efficient and effective novel therapies for medulloblastoma

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