Protective Properties of Radio-Chemoresistant Glioblastoma Stem Cell Clones Are Associated with Metabolic Adaptation to Reduced Glucose Dependence
| العنوان: | Protective Properties of Radio-Chemoresistant Glioblastoma Stem Cell Clones Are Associated with Metabolic Adaptation to Reduced Glucose Dependence |
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| المؤلفون: | 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 |
| المساهمون: | Hjelmeland, Anita B |
| المصدر: | PLoS ONE PLoS ONE, Vol 8, Iss 11, p e80397 (2013) PloS one, vol 8, iss 11 |
| بيانات النشر: | Public Library of Science (PLoS), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::58ac9e35b9604d208ef6330a487ad2eeTest https://doi.org/10.1371/journal.pone.0080397Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....58ac9e35b9604d208ef6330a487ad2ee |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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