Hypoxia-Like Signatures Induced by BCR-ABL Potentially Alter the Glutamine Uptake for Maintaining Oxidative Phosphorylation

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 transduce...

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Vydáno v:	PloS one Ročník 11; číslo 4; s. e0153226
Hlavní autoři:	Sontakke, Pallavi, Koczula, Katarzyna M., Jaques, Jennifer, Wierenga, Albertus T. J., Brouwers-Vos, Annet Z., Pruis, Maurien, Günther, Ulrich L., Vellenga, Edo, Schuringa, Jan Jacob
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 07.04.2016 Public Library of Science (PLoS)
Témata:	Abl protein Antigens, CD34 - metabolism Apoptosis BCR protein BCR-ABL 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 Netherlands
ISSN:	1932-6203, 1932-6203
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: PS JJS. Performed the experiments: PS KMK JJ ATJW AZB MP. Analyzed the data: PS KMK UG EV AZB JJS. Wrote the paper: PS JJS.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0153226