Protective Properties of Radio-Chemoresistant Glioblastoma Stem Cell Clones Are Associated with Metabolic Adaptation to Reduced Glucose Dependence

Autor: Timothy F. Cloughesy, William H. Yong, Dörthe Schaue, Jane Y. Tian, Fei Ye, William H. McBride, Linda M. Liau, Jonathan L. Tso, Stanley F. Nelson, Yue Liu, Jimmy C. Menjivar, Kazunari Yamada, Paul S. Mischel, Yibei Zhang, Cho-Lea Tso
Přispěvatelé: Hjelmeland, Anita B
Rok vydání: 2013
Předmět:
Aging
DNA Repair
Glucose uptake
Drug Resistance
lcsh:Medicine
Gene Expression
medicine.disease_cause
0302 clinical medicine
lcsh:Science
Cancer
0303 health sciences
Tumor
Multidisciplinary
Stem Cells
Adaptation
Physiological
Phenotype
Up-Regulation
Dacarbazine
Biochemistry
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
Development of treatments and therapeutic interventions
Stem cell
Research Article
Signal Transduction
General Science & Technology
DNA repair
Physiological
Biology
Stress
Cell Line
03 medical and health sciences
Rare Diseases
Downregulation and upregulation
Stress
Physiological
Cell Line
Tumor
Genetics
Temozolomide
medicine
Humans
Adaptation
Clonogenic assay
Protein kinase B
Nutrition
030304 developmental biology
lcsh:R
Stem Cell Research
Brain Disorders
Brain Cancer
Glucose
Drug Resistance
Neoplasm
Cancer research
Neoplasm
lcsh:Q
Glioblastoma
Oxidative stress
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 11, p e80397 (2013)
PloS one, vol 8, iss 11
ISSN: 1932-6203
Popis: Glioblastoma stem cells (GSC) are a significant cell model for explaining brain tumor recurrence. However, mechanisms underlying their radiochemoresistance remain obscure. Here we show that most clonogenic cells in GSC cultures are sensitive to radiation treatment (RT) with or without temozolomide (TMZ). Only a few single cells survive treatment and regain their self-repopulating capacity. Cells re-populated from treatment-resistant GSC clones contain more clonogenic cells compared to those grown from treatment-sensitive GSC clones, and repeated treatment cycles rapidly enriched clonogenic survival. When compared to sensitive clones, resistant clones exhibited slower tumor development in animals. Upregulated genes identified in resistant clones via comparative expression microarray analysis characterized cells under metabolic stress, including blocked glucose uptake, impaired insulin/Akt signaling, enhanced lipid catabolism and oxidative stress, and suppressed growth and inflammation. Moreover, many upregulated genes highlighted maintenance and repair activities, including detoxifying lipid peroxidation products, activating lysosomal autophagy/ubiquitin-proteasome pathways, and enhancing telomere maintenance and DNA repair, closely resembling the anti-aging effects of caloric/glucose restriction (CR/GR), a nutritional intervention that is known to increase lifespan and stress resistance in model organisms. Although treatment-introduced genetic mutations were detected in resistant clones, all resistant and sensitive clones were subclassified to either proneural (PN) or mesenchymal (MES) glioblastoma subtype based on their expression profiles. Functional assays demonstrated the association of treatment resistance with energy stress, including reduced glucose uptake, fatty acid oxidation (FAO)-dependent ATP maintenance, elevated reactive oxygen species (ROS) production and autophagic activity, and increased AMPK activity and NAD(+) levels accompanied by upregulated mRNA levels of SIRT1/PGC-1α axis and DNA repair genes. These data support the view that treatment resistance may arise from quiescent GSC exhibiting a GR-like phenotype, and suggest that targeting stress response pathways of resistant GSC may provide a novel strategy in combination with standard treatment for glioblastoma.
Databáze: OpenAIRE
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