Growth Factors Can Influence Cell Growth and Survival through Effects on Glucose Metabolism

Abstract

Cells from multicellular organisms are dependent upon exogenous signals for survival, growth, and proliferation. The relationship among these three processes was examined using an interleukin-3 (IL-3)-dependent cell line. No fixed dose of IL-3 determined the threshold below which cells underwent apoptosis. Instead, increasing growth factor concentrations resulted in progressive shortening of the G 1 phase of the cell cycle and more rapid proliferative expansion. Increased growth factor concentrations also resulted in proportional increases in glycolytic rates. Paradoxically, cells growing in high concentrations of growth factor had an increased susceptibility to cell death upon growth factor withdrawal. This susceptibility correlated with the magnitude of the change in the glycolytic rate following growth factor withdrawal. To investigate whether changes in the availability of glycolytic products influence mitochondrion-initiated apoptosis, we artificially limited glycolysis by manipulating the glucose levels in the medium. Like growth factor withdrawal, glucose limitation resulted in Bax translocation, a decrease in mitochondrial membrane potential, and cytochrome c redistribution to the cytosol. In contrast, increasing cell autonomous glucose uptake by overexpression of Glut1 significantly delayed apoptosis following growth factor withdrawal. These data suggest that a primary function of growth factors is to regulate glucose uptake and metabolism and thus maintain mitochondrial homeostasis and enable anabolic pathways required for cell growth. Consistent with this hypothesis, expression of the three genes involved in glucose uptake and glycolytic commitment, those for Glut1, hexokinase 2, and phosphofructokinase 1, was found to rapidly decline to nearly undetectable levels following growth factor withdrawal.

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

“…Interestingly, several known hypoxia-activated genes, such as those encoding proteins involved in glucose metabolism like Glut1, are also regulated by growth factor signaling and by notch signaling, indicating a crosstalk between those pathways (Zelzer et al, 1998;Vander Heiden et al, 2001;Fukuda et al, 2002;Ciofani and Zuniga-Pflucker, 2005). Therefore, oxygen concentration should be taken into account in the forthcoming studies on cellular differentiation.…”

Macroautophagy versus mitochondrial autophagy: a question of fate?

“…We have observed that interleukin-3 (IL-3) withdrawal in an IL-3-dependent hematopoietic cell line results in cell death by apoptosis, apparently triggered by downregulation of nutrient transporters (including Glut1, the glucose transporter) and decreased glucose utilization, mimicking growth under glucose-deficient conditions. 52 By contrast, IL-3 withdrawal in a similarly derived IL-3 dependent cell line selected from Bax À/À Bak À/À double knockout mice does not result in cell death. 9 Instead, the induction of autophagy allows prolonged survival of cells with relative preservation of mitochondrial function and provides an alternative source of energy.…”

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

“…The Bcl-2 family is composed of proapoptotic and antiapoptotic members controlling mitochondrial permeabilization (Chipuk et al, 2006). Glucose removal, by acting on the cell metabolic status, has been reported to activate the proapoptotic member, Bax (Chi et al, 2000;Vander Heiden et al, 2001). However, the link between Bcl-2 family and glucose metabolism remains unclear.…”