High glycolysis in gliomas despite low hexokinase transcription and activity correlated to chromosome 10 loss

Abstract

Summary Loss of chromosome 10 was observed in 10 out of 12 xenografted glioblastomas studied. Chromosome 10 carries the gene coding the hexokinase type I 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 (ax<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.

Glucose Withdrawal Induces Oxidative Stress followed by Apoptosis in Glioblastoma Cells but not in Normal Human Astrocytes

“…Tumors rely more on glycolysis than their normal counterparts (1,30), and defects in the mitochondrial respiratory chain may increase free radical production, resulting in oxidative stress (17,32,35). Consistent with these previous reports, glioblastoma multiformes display a 3-fold increase in glycolysis compared with normal tissue (9) and exhibit defects in respiration at various points in the electron transport chain (10). Our initial experiments confirm and expand on these observations.…”

“…High rates of glycolysis may in turn activate hypoxia-inducible factor1a -mediated gene expression (8). Furthermore, glioblastoma multiformes and their normal astrocytic counterparts seem to differ in certain aspects of glucose metabolism; specifically, glioblastoma multiformes exhibit a 3-fold increase in glycolysis (9) and display defects in respiration at various points in the electron transport chain (10). Such reports lend credence to efforts to exploit potential differences in metabolic pathways between glioblastoma multiformes and normal tissues.…”

Brain Tumor Exosomes and Microvesicles: Pleiotropic Effects from Tiny Cellular Surrogates

“…Another interesting feature is the putative presence of mitochondrial DNA contained within (and perhaps on the surface of) glioma cell line extracellular vesicles (Guescini, Genedani et al), which has also been seen in murine myoblast vesicles as reported by the same group (Guescini, Guidolin et al) ; this finding runs counter to other groups' findings (Valadi et al 2007) and will likely be somewhat controversial. However, given the high glycolytic capacity of gliomas and the distressed and non-uniform appearance and activities of their mitochondria (Oudard et al 1996;Oudard et al 1997;Ordys et al ;Santandreu et al 2008), relationships between exosomes and mitochondria in cancer cells could potentially be an area of fruitful and energetic study. In the next sections we will discuss the broad range signaling abilities, metabolic effects, and immunological properties of brain tumor exosomes/microvesicles, as well as the exosome-induced migratory and protective phenotypes cells experience upon exposure to exosomes.…”

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

“…Hence, substantial evidence exists showing that respiratory capacity is defective in gliomas. Based on their numerous findings in human glioma cell lines and tissues, the Poupon and Arismendi-Morillo groups suggested that the majority of astrocytomas are incapable of producing adequate amounts of energy through oxidative phosphorylation (Oudard et al, 1995(Oudard et al, , 1996(Oudard et al, , 1997Arismendi-Morillo and Castellano-Ramirez, 2008;ArismendiMorillo, 2009ArismendiMorillo, , 2010. Besides these ultrastructure findings, Renner et al (2010) showed that tumor cells isolated from human GBM could produce ATP in the presence of potassium cyanide.…”

“…These findings in animal models and in brain cancer patients indicate that tumor growth rate and prognosis is dependent to a significant extent on circulating glucose levels. Glucose is the prime fuel for glycolysis, which drives growth of most brain cancer (Oudard et al, 1996(Oudard et al, , 1997Seyfried and Mukherjee, 2005a). As long as circulating glucose levels remain elevated, tumor growth will be difficult to manage.…”