The Warburg effect is genetically determined in inherited pheochromocytomas

• Published in: PloS one 2009-09, Vol.4 (9), p.e7094-e7094
• Main Authors: Favier, Judith, Brière, Jean-Jacques, Burnichon, Nelly, Rivière, Julie, Vescovo, Laure, Benit, Paule, Giscos-Douriez, Isabelle, De Reyniès, Aurélien, Bertherat, Jérôme, Badoual, Cécile, Tissier, Frédérique, Amar, Laurence, Libé, Rosella, Plouin, Pierre-François, Jeunemaitre, Xavier, Rustin, Pierre, Gimenez-Roqueplo, Anne-Paule
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aerobic respiration; Aged; Analysis; Angiogenesis; Bioinformatics; Cancer; Child; Dehydrogenases; Diabetes and Endocrinology/Adrenal Cortex; DNA microarrays; Electron Transport; Energy consumption; Energy use; Enzymes; Female; Gene expression; Gene mutation; Genes; Genes, p53 - genetics; Genetic aspects; Genetic disorders; Genomes; Germ-Line Mutation; Glucose metabolism; Glycolysis; Heart failure; Homeostasis; Humans; Hypertension; Hypoxia; Kidney cancer; Kinases; Male; Metabolic pathways; Middle Aged; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Molecular Biology; Mutation; Neovascularization, Pathologic; Neuroendocrine tumors; Neurological disorders; Oligonucleotide Array Sequence Analysis; Oncology/Adrenal Cortex; Oxidative Phosphorylation; p53 Protein; Pheochromocytoma - genetics; Pheochromocytoma - physiopathology; Protein transport; Proteins; Thyroid gland; Transcription factors; Tumor proteins; Tumors; VHL protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0007094

The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas.