Glucose transporter 5 (GLUT5) overexpression has gained increasing attention due to its profound implications for tumorigenesis. This manuscript provides a comprehensive overview of the key findings and implications associated with GLUT5 overexpression in cancer. GLUT5 has been found to be upregulated in various cancer types, leading to alterations in fructose metabolism and enhanced glycolysis, even in the presence of oxygen, a hallmark of cancer cells. This metabolic shift provides cancer cells with an alternative energy source and contributes to their uncontrolled growth and survival. Beyond its metabolic roles, recent research has unveiled additional aspects of GLUT5 in cancer biology. GLUT5 overexpression appears to play a critical role in immune evasion mechanisms, which further worsens tumor progression and complicates therapeutic interventions. This dual role of GLUT5 in both metabolic reprogramming and immune modulation highlights its significance as a potential diagnostic marker and therapeutic target. Understanding the molecular mechanisms driving GLUT5 overexpression is crucial for developing targeted therapeutic strategies that can disrupt the unique vulnerabilities of GLUT5-overexpressing cancer cells. This review emphasizes the complexities surrounding GLUT5\'s involvement in cancer and underscores the pressing need for continued research to unlock its potential as a diagnostic biomarker and therapeutic target, ultimately improving cancer management and patient outcomes.

Prostate cancer (PC) is a common urinary system malignancy, and advanced PC patients had a poor prognosis due to recurrence or distant metastasis. Therefore, it\'s imperative to reveal more details in tumorigenesis and prognosis of PC patients.
The miRNA and mRNA expression profile data of 485 PC patients were obtained from The Cancer Genome Atlas database. The univariate Cox regression was applied to screen miRNAs relating to prognosis of PC. Then miRTarBase was used to predict target mRNAs of miRNAs. The hsa-mir-503/hsa-mir-1247 knockdown in 22RV1 cells was established to evaluate the effect of these two miRNAs on tumor cell migration and invasion ability. Flow cytometry was used to detect the effect of hsa-mir-503/hsa-mir-1247 knockdown on 22RV1 apoptosis rate.
Univariate Cox regression analysis identified hsa-mir-503 as a poor and hsa-mir-1247 as a favorable prognostic marker. Totally 649 target mRNAs were screened, among which DUSP19, FGF2, and SLC2A5 had a negative correlation with hsa-mir-503, while FGF2 and VSTM4 had a positive correlation with hsa-mir-1247. In 22RV1 cells, hsa-mir-503 was up-regulated, and hsa-mir-1247 was down-regulated. hsa-mir-503 knockdown attenuated the migration and invasion of 22RV1 cells, while hsa-mir-1247 knockdown exhibited the opposite effect. In addition, hsa-mir-503 knockdown promoted 22RV1 cell apoptosis. hsa-mir-1247 overexpression significantly inhibited the tumor growth of PC in vivo.
Herein, we demonstrated that hsa-mir-503 and hsa-mir-1247 could serve as new prognostic markers of PC, and hsa-mir-1247 had great potential to inhibit PC progression by suppressing the migration and invasion ability in vitro and in vivo.

OBJECTIVE: The purpose of this study was to profile genetic causal factors of acute respiratory distress syndrome (ARDS) and early predict patients at high ARDS risk.
METHODS: We performed a phenome-wide Mendelian Randomization analysis through summary statistics of an ARDS genome-wide association study (1250 cases and 1583 controls of European ancestry) and 33,150 traits. Transcriptomic data from human blood and lung tissues of a preclinical mouse model were used to validate biomarkers, which were further used to construct a prediction model and nomogram.
RESULTS: A total of 1736 traits, including 1223 blood RNA, 159 plasma proteins, and 354 non-gene phenotypes (classified by Biochemistry, Anthropometry, Disease, Nutrition and Habit, Immunology, and Treatment), exhibited a potentially causal relationship with ARDS development, which were accessible through a user-friendly interface platform called CARDS (Causal traits for Acute Respiratory Distress Syndrome). Regarding candidate blood RNA, four genes were validated, namely TMEM176B, SLC2A5, CDC45, and VSIG8, showing differential expression in blood of ARDS patients compared to controls, as well as dynamic expression in mouse lung tissues. Importantly, the addition of four blood genes and five immune cell proportions significantly improved the prediction performance of ARDS development, with 0.791 of the area under the curve from receiver-operator characteristic, compared to 0.725 for the basic model consisting of Acute Physiology and Chronic Health Evaluation (APACHE) III Score, sex, body mass index, bacteremia, and sepsis. A model-based nomogram was also developed for the clinical practice.
CONCLUSIONS: This study identifies a wide range of ARDS relevant factors and develops a promising prediction model, enhancing early clinical management and intervention for ARDS development.

Glucose transporter 5 (GLUT5) is a membrane transporter that specifically transports fructose and plays a key role in dietary fructose uptake and metabolism. In recent years, a high fructose diet has occupied an important position in the daily intake of human beings, resulting in a significant increase in the incidence of obesity and metabolic diseases worldwide. Over the past few decades, GLUT5 has been well understood to play a significant role in the pathogenesis of human digestive diseases. Recently, the role of GLUT5 in human cancer has received widespread attention, and a large number of studies have focused on exploring the effects of changes in GLUT5 expression levels on cancer cell survival, metabolism and metastasis. However, due to various difficulties and shortcomings, the molecular structure and mechanism of GLUT5 have not been fully elucidated, which to some extent prevents us from revealing the relationship between GLUT5 expression and cell carcinogenesis at the protein molecular level. In this review, we summarize the current understanding of the structure and function of mammalian GLUT5 and its relationship to intestinal diseases and cancer and suggest that GLUT5 may be an important target for cancer therapy.

BACKGROUND: Fructose is a very common sugar found in natural foods, while current studies demonstrate that high fructose intake is significantly associated with increased risk of multiple cancers and more aggressive tumor behavior, but the relevant mechanisms are not fully understood.
METHODS: Tumor-grafting experiments and in vitro angiogenesis assays were conducted to detect the effect of fructose and the conditioned medium of fructose-cultured tumor cells on biological function of vascular endothelial cells (VECs) and angiogenesis. 448 colorectal cancer specimens were utilized to analyze the relationship between Glut5 expression levels in VECs and tumor cells and microvascular density (MVD).
RESULTS: We found that fructose can be metabolized by VECs and activate the Akt and Src signaling pathways, thereby enhancing the proliferation, migration, and tube-forming abilities of VECs and thereby promoting angiogenesis. Moreover, fructose can also improve the expression of vascular endothelial growth factor (VEGF) by upregulating the production of reactive oxygen species (ROS) in colorectal cancer cells, thus indirectly enhancing the biological function of VECs. Furthermore, this pro-angiogenic effect of fructose metabolism has also been well validated in clinical colorectal cancer tissues and mouse models. Fructose contributes to angiogenesis in mouse subcutaneous tumor grafts, and MVD is positively correlated with Glut5 expression levels of both endothelial cells and tumor cells of human colorectal cancer specimens.
CONCLUSIONS: These findings establish the direct role and mechanism by which fructose promotes tumor progression through increased angiogenesis, and provide reliable evidence for a better understanding of tumor metabolic reprogramming.

Facilitative carbohydrate transporters (GLUTs, SLC2 gene family) are transmembrane proteins transporting hexoses and other sugars based on cellular metabolic demands. While a direct link between GLUTs and metabolic disorders has framed them as important biological and medicinal targets, targeting disease-relevant GLUTs remains challenging. In this study, we aimed to identify substrate-GLUT interactions that would discriminate between major fructose transporters. We examined the uptake distribution for conformational and configurational isomers of fructose using the corresponding conformationally locked fluorescently labeled mimetics as probes for assessing GLUT preferences in real time. Through comparative analysis of the uptake of the probes in the yeast-based single GLUT expression systems and the multi-GLUT mammalian cell environment, we established the ability of fructose transporters to discriminate between fructose conformers and epimers. We demonstrated that recreating the conformational and configurational mixture of fructose with molecular probes allows for the specific probe distribution, with fructofuranose mimetic being taken up preferentially through GLUT5 and β-d-fructopyranose mimetic passing through GLUT2. The uptake of α-d-fructopyranose mimetic was found to be independent of GLUT5 or GLUT2. The results of this study provide a new approach to analyzing GLUT5 and GLUT2 activity in live cells, and the findings can be used as a proof-of-concept for multi-GLUT activity screening in live cells. The research also provides new knowledge on substrate-GLUT interactions and new tools for monitoring alterations in GLUT activities.

The passive transport of glucose and related hexoses in human cells is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT3 is a high-affinity glucose transporter primarily responsible for glucose entry in neurons. Changes in its expression have been implicated in neurodegenerative diseases and cancer. GLUT3 inhibitors can provide new ways to probe the pathophysiological role of GLUT3 and tackle GLUT3-dependent cancers. Through in silico screening of an ~ 8 million compounds library against the inward- and outward-facing models of GLUT3, we selected ~ 200 ligand candidates. These were tested for in vivo inhibition of GLUT3 expressed in hexose transporter-deficient yeast cells, resulting in six new GLUT3 inhibitors. Examining their specificity for GLUT1-5 revealed that the most potent GLUT3 inhibitor (G3iA, IC50 ~ 7 µM) was most selective for GLUT3, inhibiting less strongly only GLUT2 (IC50 ~ 29 µM). None of the GLUT3 inhibitors affected GLUT5, three inhibited GLUT1 with equal or twofold lower potency, and four showed comparable or two- to fivefold better inhibition of GLUT4. G3iD was a pan-Class 1 GLUT inhibitor with the highest preference for GLUT4 (IC50 ~ 3.9 µM). Given the prevalence of GLUT1 and GLUT3 overexpression in many cancers and multiple myeloma\'s reliance on GLUT4, these GLUT3 inhibitors may discriminately hinder glucose entry into various cancer cells, promising novel therapeutic avenues in oncology.

Many chronic diseases are associated with decreased abundance of the gut commensal Faecalibacterium prausnitzii. This strict anaerobe can grow on dietary fibers, e.g., prebiotics, and produce high levels of butyrate, often associated to epithelial metabolism and health. However, little is known about other F. prausnitzii metabolites that may affect the colonic epithelium. Here, we analyzed prebiotic cross-feeding between F. prausnitzii and intestinal epithelial (Caco-2) cells in a \"Human-oxygen Bacteria-anaerobic\" coculture system. Inulin-grown F. prausnitzii enhanced Caco-2 viability and suppressed inflammation- and oxidative stress-marker expression. Inulin-grown F. prausnitzii produced excess butyrate and fructose, but only fructose efficiently promoted Caco-2 growth. Finally, fecal microbial taxonomy analysis (16S sequencing) from healthy volunteers (n = 255) showed the strongest positive correlation for F. prausnitzii abundance and stool fructose levels. We show that fructose, produced and accumulated in a fiber-rich colonic environment, supports colonic epithelium growth, while butyrate does not.

The latest data link the chronic consumption of large amounts of fructose present in food with the generation of hypertension and disturbances in carbohydrate and lipid metabolism, which promote the development of obesity, non-alcoholic fatty liver disease, insulin resistance, and type 2 diabetes. This effect is possible after fructose is absorbed by the small intestine cells and, to a lesser extent, by hepatocytes. Fructose transport is dependent on proteins from the family of glucose transporters (GLUTs), among which GLUT5 selectively absorbs fructose from the intestine. In this study, we examined the effect of four phenolic-rich extracts obtained from A. graveolens, B. juncea, and M. chamomilla on fructose uptake by Caco-2 cells. Extracts from B. juncea and M. chamomilla most effectively reduced fluorescent fructose analogue (NBDF) accumulation in Caco-2, as well as downregulated GLUT5 protein levels. These preparations were able to decrease the mRNA level of genes encoding transcription factors regulating GLUT5 expression-thioredoxin-interacting protein (TXNIP) and carbohydrate-responsive element-binding protein (ChREBP). Active extracts contained large amounts of apigenin and flavonols. The molecular docking simulation suggested that some of identified phenolic constituents can play an important role in the inhibition of GLUT5-mediated fructose transport.

Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi-Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.