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Gene & Protein in Disease GLUT5 in cancer development and therapy

also influences the expression and activity of ATP-binding 4.2. Modulation of cell survival pathways
cassette (ABC) transporters, such as P-glycoprotein (P-gp). Most chemotherapeutic drugs induce cancer cell death
These efflux pumps drive chemotherapeutic drugs out of by generating ROS. Fructose metabolism through PPP
cancer cells, reducing drug intracellular concentrations increases NADPH production, which is necessary for
and effectiveness. The upregulation of efflux pumps is a regenerating glutathione, a major cellular antioxidant.
signature of cancer drug resistance where the efflux pump Glutathione can help in neutralizing ROS and protecting
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expression can be influenced by several aspects of the cancer cells from oxidative damage induced by
fructose metabolism, including the activation of related 70
signaling pathways (e.g., PI3K/AKT), upregulation of ROS chemotherapy. NADPH also supports the activity of
production, and transcriptional regulation by HIF1α. detoxifying enzymes such as glutathione peroxidase,
Many studies have shown that the fructose-induced which neutralizes ROS and other toxic substances,
metabolic alteration was closely related to multidrug contributing to drug resistance. In addition, GLUT5-
resistant phenotype in various cancer. For example, Shen triggered high fructose utilization can cause chronic
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et al. suggested that the synergistic effects of GLUT5 and inflammation, which is known to be associated with the
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KHK during the fructose metabolism promoted the cell activation of survival pathways in cancer cells. Fructose-
proliferation and chemotherapy resistance in colorectal induced inflammation can activate the NF-κB pathway,
cancer. Weng et al. demonstrated that GLUT5 inhibition which is known to regulate the gene expression associated
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re-sensitized drug-resistant lung adenocarcinoma cells to with cell survival, proliferation, and drug resistance. These
paclitaxel treatment, a direct evidence of the role of GLUT5 pathways can also upregulate anti-apoptotic proteins and
expression in cancer drug resistance. The previous studies downregulate pro-apoptotic proteins, making cancer
have shown that fructose metabolism caused activation cells more resistant to chemotherapy. By supporting the
of the PI3K/AKT signaling pathway, which is known to activation of survival pathways, GLUT5 expression helps
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regulate efflux pump expression, such as P-gp, and serve cancer cells evade apoptosis, a key mechanism through
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as the key link modulating cancer multidrug resistance. which many chemotherapeutic agents exert their effects.
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Fructose metabolism promotes PPP activity, leading to As mentioned early, fructose metabolism activates
NADPH production and ribose-5-phosphate. NADPH PI3K/AKT pathway that inhibits pro-apoptotic signals
is crucial for maintaining redox balance and reducing and caspase activation, promoting cell survival even
oxidative stress caused by chemotherapy. Fructose under stressful conditions. For example, a study by
metabolism can activate transcription factors such as Pungsrinont et al. demonstrated the critical role
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NF-κB by ROS generation and stabilize HIF1α, which of hyperactivation of PI3K-AKT-mTOR pathway in
both can induce efflux pump expression. Some of the key regulating pro-survival/anti-apoptotic pathways of cells
process in GLUT5-associated drug resistance is illustrated as a resistance mechanism for prostate therapy. Fructose
in Figure 4. metabolism in cancer cells influences drug resistance by

increasing antioxidant defenses and mitigating oxidative
stress-induced damage. These adaptations allow cancer
cells to survive under therapeutic pressure and maintain
their proliferative capacity. Understanding the interplay
between fructose metabolism, oxidative stress, and
antioxidant mechanisms provides insights into potential
strategies to overcome drug resistance and improve
the effectiveness of cancer treatments. Shen et al.
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proposed the mechanism of GLUT5-KHK axis-mediated
fructose metabolism promoting proliferation and drug
resistance in colorectal cancer. It has been shown that
GLUT5 regulation consequent to AKT1/3-miR-125b-5p
downregulation elicited drug resistance in colorectal
cancer cells with elevated Toll-like receptor (TLR)
expression. Furthermore, fructose metabolism was
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shown to promote cytoprotection in melanoma tumors,
making them resistant to immunotherapy. Performed
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Figure 4. Illustration of pathways and key players of fructose metabolism using immune impaired C57BL/6 mouse model bearing
inducing cancer drug resistance. Created with Biorender.com B16 melanoma or MC38 carcinoma tumors, the study

Volume 3 Issue 4 (2024) 8 doi: 10.36922/gpd.4171