The Warburg effect is genetically determined in inherited pheochromocytomas.
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.
Favier
Judith
J
INSERM, Unit 970, Paris, France. judith.favier@inserm.fr
Brière
Jean-Jacques
JJ
Burnichon
Nelly
N
Rivière
Julie
J
Vescovo
Laure
L
Benit
Paule
P
Giscos-Douriez
Isabelle
I
De Reyniès
Aurélien
A
Bertherat
Jérôme
J
Badoual
Cécile
C
Tissier
Frédérique
F
Amar
Laurence
L
Libé
Rosella
R
Plouin
Pierre-François
PF
Jeunemaitre
Xavier
X
Rustin
Pierre
P
Gimenez-Roqueplo
Anne-Paule
AP
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004579:Electron Transport; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D018095:Germ-Line Mutation; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D010673:Pheochromocytoma / Q000235:genetics* / Q000503:physiopathology*