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Gene & Protein in Disease GLUT5 in cancer development and therapy

2.1. Metabolic alteration in cancer cells Typically, fructose is not a regular energy source for most

Fructose and glucose are monosaccharide isomers with cells. However, many studies have shown the upregulation
the same chemical formula (Figure 1A) but vary in their of GLUT5 in various cancer cells, considering fructose as
functional groups. The structural difference and their an additional energy source. The GLUT5 overexpression
biological function led to different metabolic pathways on cancer cells directly increases the fructose uptake and
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and processing locations. Both sugars can participate further induces metabolic alteration of cancer cells.
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in glycolysis, serving as energy and carbon sources for Fructose can enter the glycolytic pathway downstream of
biological systems, but the metabolic processes and key the rate-limiting step regulated by phosphofructokinase
enzymes are different, as shown in Figure 2B. Glucose (Figure 1B). Due to the lack of regulation, fructose can
can be metabolized by all cell types throughout the body enter glycolysis more efficiently and be metabolized
through several interconnected pathways to break down more rapidly than glucose, providing a rapid source of
glucose. Glucose metabolism is the key energy source for ATP and metabolic intermediates to support cancer
normal cells and the metabolic processes include glycolysis, cell proliferation and growth. In brief, fructose is first
pyruvate metabolism, the tricarboxylic acid (TCA) cycle, metabolized into fructose-1-phsphate (F1P) by KHK,
and oxidative phosphorylation, along with glycogenesis. In also known as fructokinase. This process also leads to uric
addition, these processes are tightly regulated to maintain acid production and stimulates the activity of glycolytic
energy homeostasis in the body. enzymes to increase the rate of glycolysis, and a subsequent
However, many types of cancer cells showed altered high ATP production rate. The F1P-induced production
metabolism where glycolysis become the main energy of uric acid can lead to oxidative stress in mitochondria,
production step even in the presence of oxygen, known as which inhibits TCA cycle, and stimulates cell proliferation.
the Warburg effect. This metabolic shift was believed to be F1P is subsequently cleaved into glyceraldehyde (GA)
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driven by much higher ATP production rate of glycolysis and dihydroxyacetone phosphate (DHAP) by aldolase B
(100 times faster) than that of TCA cycle in mitochondria. (ALDOB). These metabolites either can enter glycolysis
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The Warburg effect impacts many aspects of cancer cells, through phosphorylated GA or be converted into fat
such as proliferation, metastasis, and drug resistance. The when DHAP combines with glycerol to form glycerol-
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resulted high ATP production rate and biosynthesis are to 3-phosphate (G3P). This DHAP conversion leads to
meet the metabolic demand of fast-growing cancer cells. increased accumulation of intracellular free fatty acids.

A

B

Figure 1. The illustration of (A) structures of fructose and glucose and (B) the metabolic process and key players of the fructose and glucose. Created with
Biorender.com

Volume 3 Issue 4 (2024) 3 doi: 10.36922/gpd.4171