Regulation of energy metabolism in tumor cells : the role of hexokinase

Sammanfattning: Changes in glucose metabolism are among the most universal andfundamental metabolic alterations observed in cancer cells. Hexokinase isthe initial regulatory enzyme which controls the rate of glucose entranceinto the glycolytic pathway. The content of hexokinase in tumor cells iselevated, and most of the enzyme is bound to mitochondria. The presentstudy was directed towards understanding the significance of alteredglucose metabolism in cancer, and the physiological role played byhexokinase. Two models by which hexokinase could regulate tumorglycolysis were tested and found not tenable. The first model predictsthat glucose-6-phosphate-modulated release of hexokinase from themitochondrial surface provides kinetic control over glycolysis, since thebound and soluble enzymes exhibit different Km values for substrate. Incontrast, it was found that hexokinase is not released from mitochondriain intact hepatoma cells poised over a large range of glycolytic fluxes.The second model states that the ATP being exported from mitochondriais channeled directly to hexokinase bound at the site of export, and thatchanneling improves the efficiency of glucose phosphorylation andenhances glycolysis. It was found that bound hexokinase has no preferredaccess to ATP from oxidative phosphorylation in rapidly growing tumorcells. It was further observed that hexokinase does not plug the outermembrane pore structure to prevent metabolic exchange betweenmitochondria and cytosol. Hexokinase binding protein, porin was increasedin tumor cells, and might contribute to the elevated hexokinase activity.In addition, it was found that hexokinase is synthesized in excess ofbinding sites and that the excess enzyme is not stable. The cellularcontent of hexokinase is thus controlled by the availability ofmitochondrial binding sites.