Page 26 - GPD-3-4

Gene & Protein in Disease GLUT5 in cancer development and therapy

GLUT5 in clinical samples of prostate cancer patients the activities of several transcriptional factors through its
when compared with their benign counterparts. 13 non-canonical functions. 37,38 In this study, the PIM2 was
Besides the direct correlation of GLUT5 expression confirmed as a new binding partner of FBP1 to induce
and fructose uptake, GLUT5 overexpression also affects FBP1 phosphorylation on Ser144. As discussed earlier,
other key players of the fructose metabolism process. fructose metabolism also leads to increased lipogenesis,
For example, it has been shown that KHK protein was promoting the release of pro-inflammatory lipid mediators
upregulated by GLUT5 overexpression in colorectal cancer and cytokines. This lipid-driven inflammation and
cells by inhibiting lysosomal degradation. This GLUT5- persistent oxidative stress can suppress effective immune
9
KHK association was also observed in xenograft tumor responses and enhance tumor cell survival.
growth in vivo. Suwannakul et al. reported that fructose 3. Correlation between GLUT 5 expression
14
consumption increased xenograft tumor growth in nude and cancer metastasis
mice that was directly related to GLUT5 expression and
GLUT5-dependent downstream genes, such as KHK, The correlation between GLUT5 expression and cancer
aldolase B (ALDOB), and hypoxia-inducible factor 1 alpha metastasis lies in several critical biochemical and
(HIF1a). For example, it was shown that a deficiency in physiological mechanisms. As discussed earlier, GLUT5,
KHK-A suppressed the proliferation of gastric cancer cells the fructose-specific transporter, plays a pivotal role in
by downregulating β-catenin, a key factor in cell growth facilitating fructose uptake and metabolism in cancer cells.
and survival. GLUT5-mediated fructose utilization has Some intermediates from the fructose metabolism process
33
also been shown to induce lung cancer growth through also influence cancer cell activities, such as uric acid
enhanced lipogenesis and AMP-activated protein kinase- production, activities of MMPs, and angiogenesis. In this
16
AMPK/mTORC1 signaling. Fructose-induced mTORC1 section, we emphasize the mechanisms and key players
activation was also linked to the autophagy inhibition that directly influence GLUT5-mediated cancer metastasis.
34
that promoted pancreatic cancer progression. In this
study by Cui et al. , it was shown that GLUT5-mediated 3.1. Enhanced tumor growth and metastasis
34
fructose metabolism activated the AMPK/TORC1 Some mechanisms promoting tumor growth discussed
signaling pathway to inhibit glucose deficiency-induced in section 1 also contribute to cancer metastasis, such as
autophagy. The typical involved pathways and key players enhanced glycolysis and lipogenesis to meet the energy and
are summarized in Figure 2. biosynthesis needs of rapidly growing cells. In addition,
fructose metabolism leads to increased uric acid production,
2.3. Inflammatory and immunosuppressive effects which can induce oxidative stress and inflammation,
Fructose metabolism can activate the NF-κB (nuclear promoting a tumor-supportive environment. Uric acid
factor kappa-light-chain-enhancer of activated B-cells) also activates aldose reductase, a key enzyme of the polyol
pathway, a key regulator of inflammation. This activation pathway that converts glucose to fructose through sorbitol.
leads to the production of pro-inflammatory cytokines For example, a study by Weng et al. not only reported
15
such as interleukin (IL)-6, IL-1β, and tumor necrosis the role of GLUT5 upregulation in lung adenocarcinoma
factor-alpha (TNF-α). For example, it has been shown that patient samples and its association with poor patient
IL-6/STAT3 worked together to activate GLUT5 expression prognosis but also demonstrated the link between GLUT5
to regulate fructose metabolism and tumorigenesis. In expression and cell migration, invasion, and metastasis.
35
15
this study, a synergistic effect of inflammatory factors In another study, Jin et al. reported multiple effects of
32
and fructose metabolism in facilitating tumor growth GLUT5 expression in ovarian cancer, including cell
32
was reported in oral squamous cell carcinoma cells and proliferation, colony formation, and cell migration,
prostate cancer cells. Specifically, IL-6 treatment enhanced upregulation of GLUT5 in ovarian cancer patient samples,
GLUT5 expression through transcription factor STAT3 as well as the correlation of GLUT5 expression and tumor
transcription that associates with GLUT5 promoter malignancy and poor patient survival. Interestingly, the
region. Similarly, Lu et al. reported that fructose-1,6- high expression of GLUT1, a glucose transporter, has been
36
bisphosphatase 1 (FBP1) interacted with NF-κB p65 to observed in primary cancer, but GLUT5 has been found
regulate breast tumorigenesis through PIM2 (proviral to be upregulated in metastatic tumor, suggesting that
insertion in murine lymphomas 2) in nude mice. FBP1 GLUT5-mediated fructose metabolism greatly impacts
39
is the rate-limiting enzyme in gluconeogenesis, a glucose lung cancer metastasis. Similarly, it has been reported
formation process from non-hexose precursors (e.g., that GLUT5 overexpression promoted migration of lung
glycerol, lactate, or pyruvate). FBP1 has also recently cancer cells in vitro and reduced the overall survival of
been shown to not only suppress tumor but also regulate tumor-bearing mice. In this study, the metastatic effects

Volume 3 Issue 4 (2024) 5 doi: 10.36922/gpd.4171