Glycolysis and the pentose phosphate pathway are differentially associated with the dichotomous regulation of glioblastoma cell migration versus proliferation
Autor: | Jonathan Weller, Annegret Kathagen-Buhmann, Mareike Holz, Rainer Glass, Christel Herold-Mende, Katrin Lamszus, Alexander Schulte |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Apoptosis Mice SCID Pentose phosphate pathway Biology Pentose Phosphate Pathway Mice 03 medical and health sciences 0302 clinical medicine Basic and Translational Investigation Downregulation and upregulation Cell Movement Mice Inbred NOD Glioma Tumor Cells Cultured medicine Animals Humans Glycolysis Hypoxia Cell Proliferation Mice Hairless Gene knockdown Cell growth medicine.disease Xenograft Model Antitumor Assays Molecular biology Oxygen tension Cell biology Metabolic pathway Glucose 030104 developmental biology Oncology Neurology (clinical) Glioblastoma 030217 neurology & neurosurgery |
Zdroj: | Neuro-Oncology. 18:1219-1229 |
ISSN: | 1523-5866 1522-8517 |
Popis: | Background. The dichotomy between glioblastoma cell migration and proliferation is regulated by various parameters including oxygen tension. In glioblastoma stem-like cells, hypoxia induces downregulation of pentose phosphate pathway (PPP) enzymes and a flux shift towards glycolysis. We investigated whether the 2 parallel glucose metabolic pathways are intrinsically linked with cell function and whether these pathways are mechanistically involved in regulating functional programs. Methods. Enzyme expression, migration, and proliferation under hypoxia were studied in multiple cell types. Rapidly and slowly dividing or migrating glioblastoma cells were separated, and enzyme profiles were compared. Glucose-6-phosphate dehydrogenase (G6PD) and Aldolase C (ALDOC), the most strongly inversely regulated PPP and glycolysis enzymes, were knocked down by short hairpin RNA. Results. Hypoxia caused downregulation of PPP enzymes and upregulation of glycolysis enzymes in a broad spectrum of cancer and nonneoplastic cells and consistently stimulated migration while reducing proliferation. PPP enzyme expression was increased in rapidly dividing glioblastoma cells, whereas glycolysis enzymes were decreased. Conversely, glycolysis enzymes were elevated in migrating cells, whereas PPP enzymes were diminished. Knockdown of G6PD reduced glioblastoma cell proliferation, whereas ALDOC knockdown decreased migration. Enzyme inhibitors had similar effects. G6PD knockdown in a highly proliferative but non-invasive glioblastoma cell line resulted in prolonged survival of mice with intracerebral xenografts, whereas ALDOC knockdown shortened survival. In a highly invasive glioblastoma xenograft model, tumor burden was unchanged by either knockdown. Conclusions. Cell function and metabolic state are coupled independently of hypoxia, and glucose metabolic pathways are causatively involved in regulating "go or grow" cellular programs. |
Databáze: | OpenAIRE |
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