title: High glycolysis in gliomas despite low hexokinase transcription and activity correlated to chromosome 10 loss.
abstract: Loss of chromosome 10 was observed in 10 out of 12 xenografted glioblastomas studied. Chromosome 10 carries the gene coding the hexokinase type 1 isoenzyme (HK-I), which catalyses the first step of glycolysis, which is essential in brain tissue and glioblastomas. We investigated the relationships between the relative chromosome 10 number, the amount of HK-I mRNA, HK-I activity and its intracellular distribution, and glycolysis-related parameters such as the lactate-pyruvate ratio, lactate dehydrogenase (LDH) and ATP contents. Individual tumour HK-I mRNA amounts were 23-65% lower than that of normal human brain and reflected the relative decrease of chromosome 10 number (alpha < 0.01). Total HK activities of individual glioblastomas varied considerably but were constantly (a mean of seven times) lower than that of normal brain tissue. The mitochondria-bound HK-I fraction of individual tumours was generally over 50%, compared with that of normal brain tissue. As shown by lactate - pyruvate ratios, in all the gliomas, glycolysis was elevated to an average of 3-fold that measured in normal brain. An elevated ATP content was also constantly noted. Adaptation of glioblastoma metabolism to the chromosome 10 loss and to the HK-I transcription unit emphasises the critical role of glycolysis in their survival. We hypothesise that HK-I, the enzyme responsible for initiating glycolysis necessary for brain function, may approach its lowest limit in gliomas, thereby opening therapeutic access to pharmacological anti-metabolites affecting energy metabolism and tumour growth.
authors.affiliation: Laboratoire de Cytogénétique Moléculaire et Oncologie, UMR 147-CNRS, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Oudard
authors.forename: F
authors.initials: F
authors.lastname: Arvelo
authors.forename: L
authors.initials: L
authors.lastname: Miccoli
authors.forename: F
authors.initials: F
authors.lastname: Apiou
authors.forename: A M
authors.initials: AM
authors.lastname: Dutrillaux
authors.forename: M
authors.initials: M
authors.lastname: Poisson
authors.forename: B
authors.initials: B
authors.lastname: Dutrillaux
authors.forename: M F
authors.initials: MF
authors.lastname: Poupon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D012333:RNA, Messenger; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D006593:Hexokinase