Untitled

Abstract

Current thought is that proliferating cells undergo a shift from oxidative to glycolytic metabolism, where the energy requirements of the rapidly dividing cell are provided by ATP from glycolysis. Drawing on the hexokinase-mitochondrial acceptor theory of insulin action, this article presents evidence suggesting that the increased binding of hexokinase to porin on mitochondria of cancer cells not only accelerates glycolysis by providing hexokinase with better access to ATP, but also stimulates the TCA cycle by providing the mitochondrion with ADP that acts as an acceptor for phosphoryl groups. Furthermore, this acceleration of the TCA cycle stimulates protein synthesis via two mechanisms: first, by increasing ATP production, and second, by provision of certain amino acids required for protein synthesis, since the amino acids glutamate, alanine, and aspartate are either reduction products or partially oxidized products of the intermediates of glycolysis and the TCA cycle. The utilization of oxygen in the course of the TCA cycle turnover is relatively diminished even though TCA cycle intermediates are being consumed. With partial oxidation of TCA cycle intermediates into amino acids, there is necessarily a reduction in formation of CO2 from pyruvate, seen as a relative diminution in utilization of oxygen in relation to carbon utilization. This has been assumed to be an inhibition of oxygen uptake and therefore a diminution of TCA cycle activity. Therefore a switch from oxidative metabolism to glycolytic metabolism has been assumed (the Crabtree effect). By stimulating both ATP production and protein synthesis for the rapidly dividing cell, the binding of hexokinase to mitochondrial porin lies at the core of proliferative energy metabolism. This article further reviews literature on the binding of the isozymes of hexokinase to porin, and on the evolution of insulin, proposing that intracellular insulin-like proteins directly bind hexokinase to mitochondrial porin.

Mitochondrial Hexokinase II Promotes Neuronal Survival and Acts Downstream of Glycogen Synthase Kinase-3

“…Interestingly, HKII and an abnormally high glycolytic rate are widely considered to favor cell survival and rapid cell growth in tumor cells, thereby stimulating tumor progression (62,67). Our results now suggest that HKII is also a potent promoter of neuronal cell survival, and it can therefore be considered as a promising therapeutic target in the context of neurodegenerative diseases.…”

Expression of Glut-1 and HK-II in Pancreatic Cancer and Their Impact on Prognosis and FDG Accumulation

“…It is believed that the dephosphorylation process is negligible and the 18 F-FDG-6-P is neither transported out of cells nor subjected to glycolytic breakdown; it is metabolically trapped inside cells. Thus, 18 F-FDG accumulation depends basically on the rate of transport through the cell membrane and the activity of hexokinases [47], [48].…”

Glycolysis inhibition for anticancer treatment

“…At the protein level, hexokinases are either free in the cytosol or bound to the mitochondrial outer membrane (Wilson, 2003). The mitochondria-bond hexokinase seems to have the advantage of using ATP produced by oxidative phosphorylation as the substrate to phosphorylate glucose (Golshani-Hebroni and Bessman, 1997;Pastorino and Hoek, 2003). It was estimated that approximately 70% of cellular hexokinase is associated with mitochondria under basal metabolic conditions (Lynch et al, 1991).…”