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Gene & Protein in Disease GLUT5 in cancer development and therapy

intestine, liver, and kidney. Although adipose and muscle altered metabolic rate. Several mechanisms associated
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tissues can also metabolize fructose, metabolic pathways with GLUT5-mediated fructose metabolism have been
are different. In liver, intestine, and kidney, fructose is proposed, but GLUT5 expression seems the controlling
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phosphorylated at number 1 carbon by ketohexokinase step by directly increasing fructose utilization. Therefore,
(KHK), producing various intermediates for glycolysis GLUT5 emerges as a marker of cancer diagnosis and
or lipogenesis. In contrast, in muscle and adipose prognosis, 19,20 and inhibiting GLUT5 has been shown to
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tissue, fructose is phosphorylated at number 6 carbon by be an effective approach to treating cancer through either
hexokinase (HK), entering glycolysis, but the process is individual or combined therapy. 21
less efficient than glucose. In addition, fructose can be In this review, we focus our discussion on the impacts
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involved in polyol pathway, a reversible process between of GLUT5 expression and related pathways on cancer
glucose and fructose through intermediate of sorbitol. It progression, metastasis, and drug resistance, highlighting
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has been shown that fructose preserves the stemness of the underlying mechanisms and potential therapeutic
stem cells and decreases stem cell proliferation. 6 implications. Specifically, we first discuss the role of
Recently, increasing evidence suggested the expression GLUT5 expression and metabolic alteration in cancer
of GLUT5 in various cancer cells, resulting in fructose cells, such as enhanced glycolysis and the induced pentose
uptake and metabolism in cancer cells and affecting phosphate pathway (PPP). The altered metabolism leads
tumor development and progression. By far, GLUT5 to high energy production and enhanced biosynthesis
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overexpression has been reported in various cancers, which to support rapid cell proliferation, survival, and tumor
was believed to be induced by fructose dietary uptake. growth. GLUT5-mediated fructose metabolism promotes
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For example, fructose supplementation was shown to epithelial-mesenchymal transition (EMT), upregulates
promote GLUT5 overexpression in subcutaneous tumors matrix metalloproteinases (MMP), and increases
in nude mice The upregulation of GLUT5 in cancer cells angiogenesis, all of which are key players in cancer cell
.9
directly increases the fructose uptake rate and metabolism. invasion and metastasis. Finally, we intend to understand
Similarly, GLUT5 upregulation was observed in colorectal the contribution of the elevated fructose metabolism to
cancer patient samples compared to those from healthy chemoresistance, in particular, the involved biological
individuals. In another study, molecular imaging clearly pathways and metabolites, such as the enhanced
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demonstrated the overexpression of GLUT5 protein antioxidant defenses through NADPH production, efflux
in breast tumor in mice. An analysis of 85 glioma transporters modulation, and activation of pro-survival
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patient samples also exhibited GLUT5 upregulation in signaling pathways (e.g., PI3K/AKT). These mechanisms
glioma tissues that were directly associated with glioma allow cancer cells to survive oxidative stress induced by
malignancy and patient poor survival. Furthermore, chemotherapy. Due to the direct correlation between high
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GLUT5 was significantly upregulated in clinical samples fructose intake and GLUT5 expression, targeting GLUT5
of prostate cancer patients when compared with their and related pathways offers a promising strategy for
benign counterparts. Overexpressed GLUT5 in human improving cancer treatment outcomes.
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cholangiocarcinoma was also reported based on RNA
sequencing data from human tissue samples and cell 2. Correlation between GLUT 5 expression
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lines. Besides GLUT5 expression, its expression levels and cancer development
were reported to be closely linked to malignant evolution The correlation between GLUT5 expression and cancer
and clinical prognosis. 9,15,16 progression is closely related to fructose uptake and altered
The upregulation of GLUT5 was believed to be metabolism. GLUT5, the fructose-specific transporter,
resulted from the increased metabolic demands of rapidly facilitates fructose uptake into cancer cells, which can
proliferating cancer cells to enhance fructose uptake. impact cancer development from several aspects, such as
Compared to normal cells, cancer cells not only expressed enhanced energy production, increased cell proliferation
GLUT5 abnormally to use fructose as additional energy and survival, and immune evasion. In this section,
source but also exhibited altered metabolism known we discuss the impacts of GLUT5-mediated fructose
as the Warburg effect. The Warburg effect refers to a metabolism on the energy production and biosynthesis.
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phenomenon that cancer cells primarily use glycolysis for Both the high-energy production and accelerated
energy production even in the presence of oxygen. The biosynthesis are critical elements for fast-growing cells.
abnormal expression of GLUT5 allows using fructose as Here, the focus will be given on the effects of specific
an additional energy source and metabolic intermediates pathways and key players of the fructose metabolic process
for biosynthesis. In addition, fructose metabolism further on cancer progression.
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Volume 3 Issue 4 (2024) 2 doi: 10.36922/gpd.4171