Growth factors can influence cell growth and survival through effects on glucose metabolism

Cells from multicellular organisms are dependent upon exogenous signals for survival, growth, and proliferation. The relationship among these three pr ocesses was examined using an interleukin-3 (IL-3) -dependent cell line. No fixed dose of IL-3 determined the threshold below which cells underwent ap optosis. Instead, increasing growth factor concentrations resulted in progr essive shortening of the G(1) phase of the cell cycle and more rapid prolif erative 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 ce ll 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 glycolyt ic products influence mitochondrion-initiated apoptosis, we artificially li mited glycolysis by manipulating the glucose levels in the medium. Like gro wth factor withdrawal, glucose limitation resulted in Bax translocation, a decrease in mitochondrial membrane potential, and cytochrome c redistributi on to the cytosol. In contrast, increasing cell autonomous glucose uptake b y overexpression of Glut1 significantly delayed apoptosis following growth factor withdrawal. These data suggest that a primary function of growth fac tors is to regulate glucose uptake and metabolism and thus maintain mitocho ndrial homeostasis and enable anabolic pathways required for cell growth. C onsistent with this hypothesis, expression of the three genes involved in g lucose 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.