title: Disabled cell density sensing leads to dysregulated cholesterol synthesis in glioblastoma.
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.
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Kambach
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Halim
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: A Gesine
authors.initials: AG
authors.lastname: Cauer
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Tristan
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Orieta
authors.initials: O
authors.lastname: Celiku
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aparna H
authors.initials: AH
authors.lastname: Kesarwala
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Shankavaram
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Batchelor
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jayne M
authors.initials: JM
authors.lastname: Stommel
mesh_terms: D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D010101:Oxygen Consumption / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D002784:Cholesterol; D018844:Cyclin-Dependent Kinases
keywords: cell cycle; cholesterol metabolism; glioblastoma; oxygen utilization; pre-clinical cancer therapies