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Molecular and Cellular Biology, September 2001, p. 5899-5912, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5899-5912.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Matthew G. Vander Heiden,1,2 David R. Plas,1,2 Jeffrey C. Rathmell,1,2 Casey J. Fox,1,2 Marian H. Harris,1,2 and Craig B. Thompson1,2,*

Abramson Family Cancer Research Institute1 and Department of Cancer Biology,2 University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 30 November 2000/Returned for modification 2 February 2001/Accepted 25 May 2001

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 G1 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.

* Corresponding author. Mailing address: Abramson Family Cancer Research Institute, 450 BRB II, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-5515. Fax: (215) 746-5511. E-mail: drt{at}mail.med.upenn.edu.

Molecular and Cellular Biology, September 2001, p. 5899-5912, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5899-5912.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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