Exploring Mechanisms of Glucose Uptake Regulation and Dilution Resistance in Growing Cancer Cells

Abstract

Most cancer cells rely on aerobic glycolysis and increased glucose uptake for the production of biosynthetic precursors needed to support rapid proliferation. Increased glucose uptake and glycolytic activity may result in intracellular acidosis and increase of osmotically active substances, leading to cell swelling. This causes dilution of cellular constituents, which can markedly influence cellular reactions and the function of proteins, and hence, control mechanisms used by cancer cells to maintain a highly glycolytic phenotype must be robust to dilution. In this paper, we review the literature on cancer cell metabolism and glucose uptake, and employ mathematical modeling to examine control mechanisms in cancer cell metabolism that show robust homeostatic control in the presence of dilution. Using differential gene expression data from the Expression Atlas database, we identify the key components of glucose uptake in cancer, in order to guide the construction of a mathematical model. By simulations of this model we show that while negative feedback from downstream glycolytic metabolites to glucose transporters is sufficient for homeostatic control of glycolysis in a constant cellular volume, it is necessary to control intermediate glycolytic enzymes in order to achieve homeostatic control during growth. With a focus on glucose uptake in cancer, we demonstrate a systems biology approach to the identification, reduction, and analysis of complex regulatory systems. SIGNIFICANCE Rapid proliferation and increased glycolytic activity in cancer cells lead to dilution of cellular constituents, which can markedly influence cellular reactions and the function of proteins. Therefore, control mechanisms used by cancer cells to maintain a highly glycolytic phenotype must be robust to dilution. We construct a mathematical model of glucose uptake in cancer, and using a systems biology approach to the analysis of regulatory networks, identify the presence of integral control motifs as a means for achieving dilution resistance. Furthermore, we show that while negative feedback from downstream glycolytic metabolites to glucose transporters is sufficient for homeostatic control of glycolysis in a constant cellular volume, it is necessary to control intermediate glycolytic enzymes to achieve homeostatic control during growth.

Perfect adaptation in biology

“…PA phenomena have been widely observed in biological systems at multiple organizational levels and at multiple timescales. These include chemotaxis in E. coli (Barkai and Leibler, 1997;Alon et al, 1999) and Dictyostelium discoideum (Levchenko and Iglesias, 2002), intracellular osmolarity (Muzzey et al, 2009;You et al, 2012), sigma-70 activity (Briat et al, 2016a), ammonia uptake (Mairet, 2018), temperature control (Ni et al, 2009), copper and zinc homeostasis (Mairet, 2018), iron homeostasis (Ni et al, 2009), calcium homeostasis (El-Samad et al, 2002), and glucose uptake in growing cancer cells (Tveit et al, 2020), among several others.…”

Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity

“…As glucose transporters are one of the crucial rate-limiting checkpoints of the reprogrammed carbohydrate metabolism of neoplastic cells, targeting GLUTs, particularly GLUT1 and GLUT3, has emerged as a promising antineoplastic approach ( 6 ). Thus, several inhibiting endeavors are being envisaged to imperil glucose uptake in neoplastic cells ( 7 , 8 ). One of such strategies comprises GLUT inhibitors, being extensively explored for their antineoplastic potential ( 9 ).…”

Universal structural requirements for maximal robust perfect adaptation in biomolecular networks

“…If this stringent form of adaptation holds despite perturbations to the parameters or the structure of the network underlying the system, then this property is called robust perfect adaptation (RPA). Biological examples of RPA systems include chemotaxis in prokaryotes ( 4 , 5 ) and eukaryotes ( 6 ); intracellular osmolarity ( 7 ); stress response mechanisms ( 8 ); transcription factor σ -70 activity ( 9 ); ammonia uptake ( 10 ); copper, zinc, iron, and calcium homeostasis ( 10 – 12 ); glucose uptake ( 13 ); and pattern formation mechanisms during development ( 14 ), among others.…”