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Gene & Protein in Disease GLUT5 in cancer development and therapy

of GLUT5-mediated fructose metabolism were attributed cellular crawling movements, which is essential for tumor
to the upregulated phosphorylated AKT caused by high invasion. GLUT5-mediated fructose metabolism also
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glycolysis rate with increased lactate production. enhanced the production of pro-inflammatory cytokines
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In addition to GLUT5 expression, other key players of such as TNF-α and IL-6. These cytokines can upregulate
the fructose metabolism also affect cancer metastasis. For the expression of MMPs, particularly MMP-2 and MMP-9,
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example, aldolase B-mediated fructose metabolism causes through activation of transcription factors (e.g., NF-κB).
preferable liver metastasis of colon cancer. In addition, For example, rats fed with high fructose diet exhibited
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KHK has been shown to behave as a nuclear protein kinase elevated p65 phosphorylation, which subsequently
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to mediate fructose-induced metastasis in breast cancer. activated NFκB, inducing enhanced MMP-9 expression.
In addition to dietary intake of fructose, hyperglycemia- FBP1 has been reported to regulate Wnt/β-catenin pathway
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induced fructose formation through the polyol pathway in breast cancer, where activation of Wnt/β-Catenin
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also promoted metastatic behaviors of gastric cancer, such pathway is a signature of metastasis. GLUT5-mediated
as enhanced cell migration and invasion, cytoskeletal fructose metabolism also increases ROS production,
rearrangement, and EMT. Cells experiencing EMT gain which can activate signaling pathways that induce MMP
mesenchymal characteristics, which enhance metastatic expression. For example, ROS-mediated expression
potential. These behaviors are believed to be related to the of MMP-3 can be observed in stromal fibroblasts and
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activation of nuclear ketohexokinase-A (KHK-A) signaling cancer cells during prostate cancer progression. Fructose
pathways. The EMT is a common result of high reactive metabolism significantly impacts the activity of MMPs
oxygen species (ROS) generation by cancer cells, leading primarily through mechanisms involving inflammatory
to the formation of stem cell like-cancer cells, known as responses. It has been shown that MMP9, a downstream
cancer stem cells. Cancer stem cells typically have an target of HIF1α, was significantly upregulated to promote
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enhanced metabolism and higher metastatic potential. lung cancer progression. Thus, therapeutic strategies
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A study by Park et al. also proposed that the regulation targeting fructose metabolism or MMPs may serve as
of GLUT5 expression as a result of AKT1/3-miR-125b-5p promising strategies to manage cancer progression and
downregulation leads to increased cell migration and improve patient outcomes.
drug resistance in TLR-modified colorectal cancer cells. 3.3. Angiogenesis
Furthermore, it has been shown that fructose metabolism
promoted glycosylation of cell surface proteins, which Angiogenesis refers to the new blood vessel formation
stimulated breast cancer migration. In the same from the existing ones, playing a crucial role in cancer
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study, GLUT5-mediated fructose uptake was shown to progression and metastasis. GLUT5-mediated fructose
influence the arrangement of glycan and cytoskeletal uptake and metabolism is known to stimulate the
proteins in breast cancer cells, promoting sialylation by production of vascular endothelial growth factor (VEGF),
increasing the expression of sialyltransferase. Therefore, promoting angiogenesis. For example, an analysis of over
the GLUT5 expression and fructose metabolism worked 400 colorectal cancer specimens suggested that the levels
synergistically to impact cancer metastasis, as illustrated of GLUT5 expression in vascular endothelial cells (VECs)
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in Figure 3. In addition to inhibiting GLUT5, targeting positively correlated with microvascular density. Several
downstream enzymes may be another viable approach in aspects of fructose metabolism are believed to contribute
cancer treatment. 46 to the increased microvascular density. First, metabolites
from fructose metabolism by VECs activate the ATK and
3.2. Activity of MMP Src signaling pathways that led to the enhancement of VEC
GLUT5-mediated fructose metabolism naturally enhances proliferation, migration, and vascular formation, thus
the production of uric acid and lactate, fostering an promoting angiogenesis. Second, the fructose metabolism
acidic tumor microenvironment. The acidic tumor in colorectal cancer cells increased ROS production,
microenvironment can increase the proteolytic activity promoting VEGF expression. These hypotheses were
of extracellular digestive enzymes, accelerating the further validated in clinical colorectal cancer tissues and
degradation of extracellular matrix (ECM) and facilitating mouse models. Many other studies also suggested that ATK
cancer metastasis. 47,48 Extracellular acidification directly signaling pathways play a key role in tumor cell migration
influences the expression and activity of MMPs, which and invasion. 58,59 It has also been shown that fructose
are enzymes for ECM degradation, facilitating cancer metabolism in tumor endothelial cells (ECs) promoted
cell invasion and migration. In addition, the altered angiogenesis by AMPK activation and mitochondrial
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tumor microenvironment is important to the function respiration. The effects were associated with the
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of invadopodia, an actin-rich structure important for overexpression of GLUT5 and KHK, the key metabolizing
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Volume 3 Issue 4 (2024) 6 doi: 10.36922/gpd.4171