Glucose Catabolism in Cancer Cells

Abstract

One of the most common signatures of highly malignant tumors is their capacity to metabolize more glucose to lactic acid than their tissues of origin. Hepatomas exhibiting this phenotype are dependent on the high expression of type II hexokinase, which supplies such tumors with abundant amounts of glucose 6-phosphate, a significant carbon and energy source especially under hypoxic conditions. Here we report that the distal region of the hepatoma type II hexokinase promoter displays consensus motifs for hypoxia-inducible factor (HIF-1) that overlap E-box sequences known to be related in other gene promoters to glucose response. Moreover, we show that subjecting transfected hepatoma cells to hypoxic conditions activates the type II hexokinase promoter almost 3-fold, a value that approaches 7-fold in the presence of glucose. Consistent with these findings is the induction under hypoxic conditions of the HIF-1 protein. Reporter gene analyses with a series of nested deletion mutants of the hepatoma type II hexokinase promoter show that a significant fraction of the total activation observed under hypoxic conditions localizes to the distal region where the overlapping HIF-1/E-box sequences are located. Finally, DNase I footprint analysis with a segment of the promoter containing these elements reveals the binding of several nuclear proteins. In summary, these novel studies identify and characterize a marked glucose-modulated activation response of the type II hexokinase gene to hypoxic conditions within highly glycolytic hepatoma cells, a property that may help assure that such cells exhibit a growth and survival advantage over their parental cells of origin.Numerous studies have demonstrated that highly malignant tumors, i.e. those that are poorly differentiated and grow rapidly, exhibit the capacity to metabolize glucose to lactate at much higher rates than normal cells (reviewed in Refs.

Metabolic Stress Induces the Lysosomal Degradation of Neuropilin-1 but Not Neuropilin-2

“…1A). In contrast, hypoxia increased the expression of hexokinase II in SUM159 cells, a hypoxiainducible glycolytic enzyme (22), providing a positive control for the hypoxic environment (Fig. 1A).…”

FDG-PET and CT features of non-small cell lung cancer based on tumor type

“…Cancer cells preferably utilize anaerobic glycolysis for energy (18) and rely on both increased glucose transport across the cell membrane (19) and enhanced hexokinase activity (20) to meet higher glucose demand. Prior studies have reported on the variation of FDG uptake based on lung cancer grade 4 (21).…”

Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

“…Significantly, functional response elements for hypoxia (HIF-1), and p53 were located on the distal region of the promoter with the proximal region also being signficantly implicated in the hypoxic response (Mathupala et al, 1997a(Mathupala et al, , 2001). Reporter gene analysis also revealed an activation of the HK II promoter by glucose and the opposing metabolic hormones insulin and glucagon as well as cAMP analogs, the latter implicating the involvement of PKA and PKC pathways (Mathupala et al, 1995;Rempel et al, 1996b).…”