Growth factors can influence cell growth and survival through effects on glucose metabolism
Open accessAbstract
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.
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As glucose uptake and usage are under growth factor control, this observation raises the possibility that a basal level of TCA cycle oxidation in cells can persist independent of exogenous growth factor stimulation.
“As glucose uptake and usage are under growth factor control (58, 59, 60), this observation raises the possibility that a basal level of TCA cycle oxidation in cells can persist independent of exogenous growth factor stimulation.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [60]
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Self-citation
- Authors
- Vander Heiden, M. G., Plas, D. R., Rathmell, J. C., Fox, C. J., Harris, M. H., & Thompson, C. B.
- Affiliations
- Abramson Family Cancer Research Institute
- University of Pennsylvania (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2001-09
- Volume
- 21
- Issue
- 17
- Pages
- 5899-5912
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC87309
- OpenAlex
- W2171674055
- Cited by
- 536
- References
- 27
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 23 · 2023: 16 · 2022: 9 · 2021: 15 · 2020: 15 · 2019: 12 · 2018: 15 · 2017: 21 · 2016: 17 · 2015: 26 · 2014: 31 · 2013: 18 · 2012: 25
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Chicago
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- growth factors, glucose metabolism, glycolysis, apoptosis, interleukin-3, cell cycle, G1 phase, growth factor withdrawal, glucose uptake, GLUT1, Bax translocation, mitochondrial membrane potential, cytochrome c, mitochondrial homeostasis, hexokinase 2, phosphofructokinase-1, cell survival, cell proliferation
- MeSH terms
- Animals, Cell Division, Cell Line, Cell Survival, Cells, Dose-Response Relationship, Drug, Glucose, Glycolysis, Interleukin-3, Mitochondria, Apoptosis, Mice
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