Disabled cell density sensing leads to dysregulated cholesterol synthesis in glioblastoma
| Autor: | Alan S. Halim, Carlos A. Tristan, Jayne M. Stommel, Uma Shankavaram, A. Gesine Cauer, Eric Batchelor, Orieta Celiku, Diane M. Kambach, Qian Sun, Aparna H. Kesarwala |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cell Count Biology Cholesterol Synthesis Inhibition High cholesterol 03 medical and health sciences chemistry.chemical_compound Oxygen Consumption Internal medicine Glioma medicine Tumor Cells Cultured Humans Protein Kinase Inhibitors Cholesterol Kinase Brain Neoplasms glioblastoma Cell Cycle Checkpoints Cell cycle medicine.disease pre-clinical cancer therapies Cyclin-Dependent Kinases 030104 developmental biology Endocrinology Cell Transformation Neoplastic Oncology chemistry Anaerobic glycolysis oxygen utilization Astrocytes Cancer research cholesterol metabolism cell cycle Mevalonate pathway Glycolysis Cell Division Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Diane M. Kambach 1 , Alan S. Halim 1 , A. Gesine Cauer 1 , Qian Sun 1 , Carlos A. Tristan 1 , Orieta Celiku 1 , Aparna H. Kesarwala 1 , Uma Shankavaram 1 , Eric Batchelor 2 , Jayne M. Stommel 1 1 Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA 2 Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Correspondence to: Jayne M. Stommel, email: jayne.stommel@nih.gov Keywords: cholesterol metabolism, oxygen utilization, glioblastoma, pre-clinical cancer therapies, cell cycle Received: August 10, 2016 Accepted: January 10, 2017 Published: January 19, 2017 ABSTRACT A hallmark of cellular transformation is the evasion of contact-dependent inhibition of growth. To find new therapeutic targets for glioblastoma, we looked for pathways that are inhibited by high cell density in astrocytes but not in glioma cells. Here we report that glioma cells have disabled the normal controls on cholesterol synthesis. At high cell density, astrocytes turn off cholesterol synthesis genes and have low cholesterol levels, but glioma cells keep this pathway on and maintain high cholesterol. Correspondingly, cholesterol pathway upregulation is associated with poor prognosis in glioblastoma patients. Densely-plated glioma cells increase oxygen consumption, aerobic glycolysis, and the pentose phosphate pathway to synthesize cholesterol, resulting in a decrease in reactive oxygen species, TCA cycle intermediates, and ATP. This constitutive cholesterol synthesis is controlled by the cell cycle, as it can be turned off by cyclin-dependent kinase inhibitors and it correlates with disabled cell cycle control though loss of p53 and RB. Finally, glioma cells, but not astrocytes, are sensitive to cholesterol synthesis inhibition downstream of the mevalonate pathway, suggesting that specifically targeting cholesterol synthesis might be an effective treatment for glioblastoma. |
| Databáze: | OpenAIRE |
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