PloS one, 2016-04, Vol.11 (4), p.e0153226-e0153226
2016
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- Autor(en) / Beteiligte
- Titel
- Hypoxia-Like Signatures Induced by BCR-ABL Potentially Alter the Glutamine Uptake for Maintaining Oxidative Phosphorylation
- Ist Teil von
- PloS one, 2016-04, Vol.11 (4), p.e0153226-e0153226
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2016
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The Warburg effect is probably the most prominent metabolic feature of cancer cells, although little is known about the underlying mechanisms and consequences. Here, we set out to study these features in detail in a number of leukemia backgrounds. The transcriptomes of human CB CD34+ cells transduced with various oncogenes, including BCR-ABL, MLL-AF9, FLT3-ITD, NUP98-HOXA9, STAT5A and KRASG12V were analyzed in detail. Our data indicate that in particular BCR-ABL, KRASG12V and STAT5 could impose hypoxic signaling under normoxic conditions. This coincided with an upregulation of glucose importers SLC2A1/3, hexokinases and HIF1 and 2. NMR-based metabolic profiling was performed in CB CD34+ cells transduced with BCR-ABL versus controls, both cultured under normoxia and hypoxia. Lactate and pyruvate levels were increased in BCR-ABL-expressing cells even under normoxia, coinciding with enhanced glutaminolysis which occurred in an HIF1/2-dependent manner. Expression of the glutamine importer SLC1A5 was increased in BCR-ABL+ cells, coinciding with an increased susceptibility to the glutaminase inhibitor BPTES. Oxygen consumption rates also decreased upon BPTES treatment, indicating a glutamine dependency for oxidative phosphorylation. The current study suggests that BCR-ABL-positive cancer cells make use of enhanced glutamine metabolism to maintain TCA cell cycle activity in glycolytic cells.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0153226Titel-ID: cdi_plos_journals_1779457480
- Format
- –
- Schlagworte
- Abl protein, Antigens, CD34 - metabolism, Apoptosis, BCR protein, Biology and Life Sciences, Blotting, Western, Cancer, Cancer cells, CD34 antigen, Cell Cycle, Cell Proliferation, Cells, Cultured, Ethics, Fetal Blood - cytology, Fetal Blood - metabolism, Fusion protein, Fusion Proteins, bcr-abl - genetics, Fusion Proteins, bcr-abl - metabolism, Gene expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic aspects, Glutaminase, Glutamine, Glutamine - metabolism, Glycolysis, Hematology, Humans, Hypoxia, Hypoxia - physiopathology, Hypoxia-inducible factor 1, Immunoenzyme Techniques, Infant, Newborn, Kinases, Lactic acid, Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology, Leukemia, Myeloid, Acute - genetics, Leukemia, Myeloid, Acute - metabolism, Leukemia, Myeloid, Acute - pathology, Magnetic Resonance Spectroscopy, Medical research, Metabolism, Metabolomics, Mutation, Neoplasm Proteins - genetics, Neoplasm Proteins - metabolism, NMR, Nuclear magnetic resonance, Oxidative Phosphorylation, Oxygen, Oxygen consumption, Phosphorylation, Physical Sciences, Physiological aspects, Pyruvic acid, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger - genetics, Signal Transduction, Signaling, Stat5 protein, Stem cells, Studies