RESUMO
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.
Assuntos
Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 5 , Neoplasias , Humanos , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Transportador de Glucose Tipo 5/metabolismo , Transportador de Glucose Tipo 5/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Glicólise , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
MicroRNAs , Neoplasias da Próstata , Masculino , Humanos , Fator 2 de Crescimento de Fibroblastos/genética , MicroRNAs/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/diagnóstico , RNA Mensageiro , Regulação Neoplásica da Expressão Gênica , Fosfatases de Especificidade Dupla/genética , Transportador de Glucose Tipo 5/genéticaRESUMO
Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Criança , Mutação , Leucemia Mieloide Aguda/patologia , Prognóstico , Estimativa de Kaplan-Meier , Proteína Supressora de Tumor p53/genética , Transportador de Glucose Tipo 5/genética , Ubiquitina-Proteína Ligases/genética , Proteínas de Ligação a Retinoblastoma/genéticaRESUMO
BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare and marginal cutaneous sarcoma of intermediate-grade malignancy, for which the genomic landscape remains unclear. Understanding the landscape of DFSP will help to further classify the genomic pathway of malignant development in soft tissue. OBJECTIVES: To identify the comprehensive molecular pathogenesis of DFSP. METHODS: In this study, the comprehensive genomic features, with 53 tumour-normal pairs of DFSP, were revealed by whole-genome sequencing. RESULTS: The mutational signature 1 (C > T mutation at CpG dinucleotides) is featured in DFSP, resulting in higher mutations in DNA replication. Interestingly, the recurrence of DFSP is correlated with low tumour mutation burden. Novel mutation genes in DFSP were identified, including MUC4/6, KMT2C and BRCA1, and subsequently, three molecular subtypes of DFSP were classified on the basis of MUC4 and MUC6 mutations. Various structural aberrations including genomic rearrangements were identified in DSFPs, particularly in 17q and 22q, which cause oncogene amplification (AKT1, SPHK1, COL1A1, PDGFß) or tumour suppressor deletion (CDKN2A/B). In addition to gene fusion of COL1A1-PDGFß [t(17;22)], we identified gene fusion of SLC2A5-BTBD7 [t(1;14)] in DFSP through whole-genome sequencing, and verified it experimentally. Enrichment analysis of altered molecules revealed that DNA repair, cell cycle, phosphoinositide 3-kinase and Janus kinase pathways were primarily involved in DFSP. CONCLUSIONS: This is the first large-scale whole-genome sequencing for DFSP, and our findings describe the comprehensive genomic landscape, highlighting the molecular complexity and genomic aberrations of DFSP. Our findings also provide novel potential diagnostic and therapeutic targets for this disease. What is already known about this topic? Chromosomal translocation between chromosome 17 and chromosome 22 is the main feature in the pathogenesis of dermatofibrosarcoma protuberans (DFSP). What does this study add? We describe the comprehensive genomic landscape of DFSP, highlighting the molecular complexity and genomic aberrations. Our findings provide novel potential diagnostic and therapeutic targets for this disease. What is the translational message? Our study revealed novel molecular subtypes of DFSP based on genetic mutations, which benefits precision diagnosis. We also found oncogene amplification, including AKT1 and SPHK1, which provides novel potential target molecules for further DFSP treatment. In addition to gene fusion of COL1A1-PDGFß, we identified a novel gene fusion of SLC2A5-BTBD7 in DFSP, which is a novel potential diagnostic and therapeutic target for this disease.
Assuntos
Dermatofibrossarcoma , Neoplasias Cutâneas , Proteínas Adaptadoras de Transdução de Sinal/genética , Dermatofibrossarcoma/genética , Dermatofibrossarcoma/patologia , Rearranjo Gênico , Genômica , Transportador de Glucose Tipo 5/genética , Humanos , Proteínas de Fusão Oncogênica/genética , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
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.
Assuntos
Descoberta de Drogas , Transportador de Glucose Tipo 3/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 2/antagonistas & inibidores , Transportador de Glucose Tipo 2/química , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 3/antagonistas & inibidores , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 3/metabolismo , Transportador de Glucose Tipo 4/antagonistas & inibidores , Transportador de Glucose Tipo 4/química , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Transportador de Glucose Tipo 5/antagonistas & inibidores , Transportador de Glucose Tipo 5/química , Transportador de Glucose Tipo 5/genética , Transportador de Glucose Tipo 5/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Microglia play a role in the regulation of metabolism and pathogenesis of obesity. Microglial activity is altered in response to changes in diet and the body's metabolic state. Solute carrier family 2 member 5 (Slc2a5) that encodes glucose transporter 5 (GLUT5) is a fructose transporter primarily expressed in microglia within the central nervous system. However, little is known about the nutritional regulation of Slc2a5 expression in microglia and its role in the regulation of metabolism. The present study aimed to address the hypothesis that nutrients affect microglial activity by altering the expression of glucose transporter genes. Murine microglial cell line SIM-A9 cells and primary microglia from mouse brain were exposed to different concentrations of glucose and levels of microglial activation markers and glucose transporter genes were measured. High concentration of glucose increased levels of the immediate-early gene product c-Fos, a marker of cell activation, Slc2a5 mRNA, and pro-inflammatory cytokine genes in microglial cells in a time-dependent manner, while fructose failed to cause these changes. Glucose-induced changes in pro-inflammatory gene expression were partially attenuated in SIM-A9 cells treated with the GLUT5 inhibitor. These findings suggest that an increase in local glucose availability leads to the activation of microglia by controlling their carbohydrate sensing mechanism through both GLUT5-dependent and -independent mechanisms.
Assuntos
Transportador de Glucose Tipo 5/genética , Glucose/farmacologia , Microglia/citologia , Animais , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas Proto-Oncogênicas c-fos/genéticaRESUMO
Lung adenocarcinoma (LUAD) is a major subtype of lung cancer with a relatively poor prognosis, requiring novel therapeutic approaches. Great advances in new immunotherapy strategies have shown encouraging results in lung cancer patients. This study is aimed at elucidating the function of SLC2A5 in the prognosis and pathogenesis of LUAD by analyzing public databases. The differential expression of SLC2A5 in various tissues from Oncomine, GEPIA, and other databases was obtained, and SLC2A5 expression at the protein level in normal and tumor tissues was detected with the use of the HPA database. Then, we used the UALCAN database to analyze the expression of SLC2A5 in different clinical feature subgroups. Notably, in both PrognoScan and Kaplan-Meier plotter databases, we found a certain association between SLC2A5 and poor OS outcomes in LUAD patients. Studies based on the TIMER database show a strong correlation between SLC2A5 expression and various immune cell infiltrates and markers. The data analysis in the UALCAN database showed that the decreased promoter methylation level of SLC2A5 in LUAD may lead to the high expression of SLC2A5. Finally, we used the LinkedOmics database to evaluate the SLC2A5-related coexpression and functional networks in LUAD and to investigate their role in tumor immunity. These findings suggest that SLC2A5 correlated with immune infiltration can be used as a candidate diagnostic and prognostic biomarker in LUAD patients.
Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 5/genética , Sistema Imunitário/metabolismo , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Transportador de Glucose Tipo 5/metabolismo , Humanos , Sistema Imunitário/citologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
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.
Assuntos
Descoberta de Drogas , Transportador de Glucose Tipo 2/antagonistas & inibidores , Transportador de Glucose Tipo 5/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Simulação por Computador , Diabetes Mellitus/tratamento farmacológico , Síndrome de Fanconi/tratamento farmacológico , Glucose/genética , Glucose/metabolismo , Transportador de Glucose Tipo 2/química , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/ultraestrutura , Transportador de Glucose Tipo 5/química , Transportador de Glucose Tipo 5/genética , Transportador de Glucose Tipo 5/ultraestrutura , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Conformação Proteica/efeitos dos fármacos , Interface Usuário-ComputadorRESUMO
The Western diet has been suggested to contribute to the rising incidence of inflammatory bowel diseases. This has led to the hypothesis that fructose, a component of the Western diet, could play a role in the pathogenesis of inflammatory bowel diseases. A high-fructose diet is known to exacerbate experimental colitis. This study tested whether the expression of GLUT5, the fructose transporter, is a determinant of the severity of experimental colitis during elevated fructose consumption and whether ileal inflammation is associated with altered GLUT5 expression in Crohn's disease. Studies in genetically engineered mice showed that in comparison to Glut5+/+ mice, feeding a 15 kcal% fructose diet to Glut5-/- mice led to worse dextran sodium sulfate (DSS)-induced colitis. This effect was associated with elevated levels of colonic fructose and a shift in the fecal microbiota in Glut5-/- mice. Importantly, treatment with broad-spectrum antibiotics protected against the worsening of colitis mediated by dietary fructose in Glut5-/- mice. Gene expression analysis revealed that GLUT5 levels are reduced in the intestines of patients with ileal Crohn's disease. Moreover, levels of GLUT5 negatively correlated with expression of proinflammatory mediators in these samples. Collectively, these results demonstrate that dietary constituent (fructose)-host gene (GLUT5) interactions can shape the colonic microbiota, thereby impacting the severity of colitis.NEW & NOTEWORTHY This study provides the first evidence that reduced levels of GLUT5, the fructose transporter, worsen experimental colitis upon fructose feeding, an effect mediated by changes in the gut microbiota. Moreover, GLUT5 expression is reduced in Crohn's ileitis. Overall, these findings demonstrate the importance of interactions between dietary fructose and host GLUT5 as determinants of both the composition of colonic microbiota and severity of experimental colitis.
Assuntos
Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Frutose/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Animais , Colite Ulcerativa/etiologia , Açúcares da Dieta/efeitos adversos , Açúcares da Dieta/metabolismo , Frutose/efeitos adversos , Microbioma Gastrointestinal , Transportador de Glucose Tipo 5/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Dodecilsulfato de Sódio/toxicidadeRESUMO
BACKGROUND: SLC2A5 is a high-affinity fructose transporter, which is frequently upregulated in multiple human malignant tumours. However, the function and molecular mechanism of SLC2A5 in colorectal cancer (CRC) remain unknown. METHODS: We detected the expression levels of SLC2A5 in CRC tissues and CRC cell lines by western blotting, qRT-PCR and immunohistochemistry. CRC cell lines with stable overexpression or knockdown of SLC2A5 were constructed to evaluate the functional roles of SLC2A5 in vitro through conventional assays. An intrasplenic inoculation model was established in mice to investigate the effect of SLC2A5 in promoting metastasis in vivo. Methylation mass spectrometry sequencing, methylation specific PCR, bisulphite sequencing PCR, ChIP-qPCR and luciferase reporter assay were performed to investigate the molecular mechanism underlying transcriptional activation of SLC2A5. RESULTS: We found that SLC2A5 was upregulated in colorectal tumour tissues. Functionally, a high level of SLC2A5 expression was associated with increased invasion and metastasis capacities of CRC cells both in vitro and in vivo. Mechanistically, we unveiled that S100P could integrate to a specific region of SLC2A5 promoter, thereby reducing its methylation levels and activating SLC2A5 transcription. CONCLUSIONS: Our results reveal a novel mechanism that S100P mediates the promoter demethylation and transcription activation of SLC2A5, thereby promoting the metastasis of CRC.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias Colorretais/patologia , Metilação de DNA , Transportador de Glucose Tipo 5/genética , Transportador de Glucose Tipo 5/metabolismo , Proteínas de Neoplasias/metabolismo , Regulação para Cima , Animais , Células CACO-2 , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Regiões Promotoras Genéticas , Ativação TranscricionalRESUMO
Clinical localization of primary tumors and sites of metastasis by PET is based on the enhanced cellular uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (FDG). In prostate cancer, however, PET-FDG imaging has shown limited clinical applicability, suggesting that prostate cancer cells may utilize hexoses other than glucose, such as fructose, as the preferred energy source. Our previous studies suggested that prostate cancer cells overexpress fructose transporters, but not glucose transporters, compared with benign cells. Here, we focused on validating the functional expression of fructose transporters and determining whether fructose can modulate the biology of prostate cancer cells in vitro and in vivo. Fructose transporters, Glut5 and Glut9, were significantly upregulated in clinical specimens of prostate cancer when compared with their benign counterparts. Fructose levels in the serum of patients with prostate cancer were significantly higher than healthy subjects. Functional expression of fructose transporters was confirmed in prostate cancer cell lines. A detailed kinetic characterization indicated that Glut5 represents the main functional contributor in mediating fructose transport in prostate cancer cells. Fructose stimulated proliferation and invasion of prostate cancer cells in vitro. In addition, dietary fructose increased the growth of prostate cancer cell line-derived xenograft tumors and promoted prostate cancer cell proliferation in patient-derived xenografts. Gene set enrichment analysis confirmed that fructose stimulation enriched for proliferation-related pathways in prostate cancer cells. These results demonstrate that fructose promotes prostate cancer cell growth and aggressiveness in vitro and in vivo and may represent an alternative energy source for prostate cancer cells. SIGNIFICANCE: This study identifies increased expression of fructose transporters in prostate cancer and demonstrates a role for fructose as a key metabolic substrate supporting prostate cancer cells, revealing potential therapeutic targets and biomarkers.
Assuntos
Biomarcadores Tumorais/metabolismo , Dieta/efeitos adversos , Frutose/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Neoplasias da Próstata/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Ciclo Celular , Movimento Celular , Proliferação de Células , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportador de Glucose Tipo 5/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS: The solute carrier family 2 (SLC2) genes are comprised of 14 members which are essential for the maintenance of glucose uptake and survival of tumour cells. This study was performed to investigate the associations of SLC2 family gene expression with mortality in acute myeloid leukemia (AML). METHODS: Clinical features and SLC2 family gene expression data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus database. The associations between SLC2 family gene expression and clinicopathologic features were analyzed using linear regression model. Kaplan-Meier survival, univariate, multivariate survival analyses and validation analysis were performed to analyze the associations between SLC2 family gene expression and patients' overall survival. RESULTS: Patient mortality was positively associated with age and cytogenetic risk in AML patients. Kaplan-Meier survival analysis suggested that patients with high SLC2A5 and SLC2A10 expression showed poorer survival than those with low SLC2A5 and SLC2A10 expression. In contrast, patients with high SLC2A13 expression exhibited better prognosis than those with low SLC2A13 expression (P < 0.05 for all cases, log rank test). Multivariate survival analysis and validation analysis confirmed that high expression of SLC2A5 and SLC2A10 and low expression of SLC2A13 were associated with increased mortality (P = 0.00, Odd ratio [OR]:4.05, 95% Confidence Interval [CI]: 1.73-10.22; P = 0.00, OR: 3.66, 95% CI: 1.54-9.25; and P = 0.01, OR: 0.26, 95% CI: 0.09-0.68, respectively). CONCLUSION: SLC family gene expression, such as SLC2A5, SLC2A10 and SLC2A13, was significantly associated with prognosis of AML patients, their expression levels might become useful prognostic biomarkers in AML.
Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportador de Glucose Tipo 5/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Bases de Dados Genéticas/estatística & dados numéricos , Feminino , Perfilação da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Objectives: Dysfunctional metabolism of carbohydrates is a fundamental component of many dietary-related disorders. It has been hypothesized that plant extracts containing high levels of antioxidants may have the ability to stabilize carbohydrate regulation. The aim of this study was to assess the effects of a polyphenol-rich sugarcane extract on cellular pathways related to carbohydrate metabolism.Methods: We evaluated the antioxidant activity of a polyphenol-rich sugarcane extract obtained by a patented hydrophobic extract process and its therapeutic potential to regulate carbohydrate metabolism and protect against metabolic disorders such as type 2 diabetes.Results: Quantitative analytical studies support that the polyphenol-rich sugarcane extract has a high concentration of polyphenols and antioxidant compounds. The follow-up cellular studies via Caco-2 cells and dysfunctional ß-cell models suggested that the polyphenol-rich sugarcane extract may help deter glucose and fructose uptake in intestinal cells and restore insulin production in dysfunctional ß-cells-key functions in managing diabetic conditions.Conclusions: These findings suggest that sugarcane polyphenols may modulate cellular mechanism in a manner that is beneficial to health.
Assuntos
Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Extratos Vegetais/química , Polifenóis/farmacologia , Saccharum/química , Animais , Antioxidantes/química , Linhagem Celular , Cromatografia Líquida , Cricetinae , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 5/genética , Transportador de Glucose Tipo 5/metabolismo , Humanos , Hipoglicemiantes/química , Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Espectrometria de Massas , Polifenóis/químicaRESUMO
To study glycolysis/glycogenesis-related genes expression in childhood B-cell acute lymphoblastic leukaemia (B-ALL), we performed a microarray-based analysis using published gene expression profiles. We found that SLC2A5, which encodes solute carrier family 2 member 5 (SLC2A5, previously termed GLUT5) that facilitates cell fructose uptake, was up-regulated in Philadelphia chromosome-positive ALL (Ph+ALL). Microarray-based analyses also suggested that SLC2A5 expression was significantly down-regulated in childhood B-ALL with t(1;19) or 11q23 mutation. High SLC2A5 expression was found in patients who had disease recurrence within 3 years, early relapse, shortened complete remission duration and positive minimal residue disease (MRD) status after treatment. SLC2A5 overexpression at both the mRNA and protein level in Ph+ALL was confirmed in a validation cohort of childhood B-ALL. We also validated the correlation of SLC2A5 expression and MRD status. A mechanistic study using a human Ph+ALL cell line showed that BCR-ABL1 kinase might regulate SLC2A5 expression via MYC. The tyrosine kinase inhibitors (TKIs) imatinib and dasatinib repressed SLC2A5 expression and the cell uptake of fructose. Fructose protected the tumour cells from nutrition deficiency and drug-induced cell death. Overall, our findings showed that SLC2A5 was up-regulated in childhood Ph+ALL. SLC2A5 expression correlated with childhood B-ALL clinical factors, such as MRD status. Given that TKIs could inhibit SLC2A5 expression, repression of fructose utility after TKI treatment contributes to TKI-induced Ph+ALL cytotoxicity. Targeting SLC2A5 might be promising in B-ALL treatment, especially for Ph+ALL patients with high SLC2A5 expression.
Assuntos
Transportador de Glucose Tipo 5/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Criança , Pré-Escolar , Feminino , Frutose/metabolismo , Proteínas de Fusão bcr-abl/fisiologia , Perfilação da Expressão Gênica/métodos , Regulação Leucêmica da Expressão Gênica , Transportador de Glucose Tipo 5/genética , Humanos , Lactente , Masculino , Mutação , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Recidiva , Células Tumorais Cultivadas , Regulação para CimaRESUMO
SCOPE: Known pharmacological activities of guava (Psidium guajava) include modulation of blood glucose levels. However, mechanistic details remain unclear in many cases. METHODS AND RESULTS: This study investigated the effects of different guava leaf and fruit extracts on intestinal glucose transport in vitro and on postprandial glucose levels in vivo. Substantial dose- and time-dependent glucose transport inhibition (up to 80%) was observed for both guava fruit and leaf extracts, at conceivable physiological concentrations in Caco-2 cells. Using sodium-containing (both glucose transporters, sodium-dependent glucose transporter 1 [SGLT1] and glucose transporter 2 [GLUT2], are active) and sodium-free (only GLUT2 is active) conditions, we show that inhibition of GLUT2 was greater than that of SGLT1. Inhibitory properties of guava extracts also remained stable after digestive juice treatment, indicating a good chemical stability of the active substances. Furthermore, we could unequivocally show that guava extracts significantly reduced blood glucose levels (≈fourfold reduction) in a time-dependent manner in vivo (C57BL/6N mice). Extracts were characterized with respect to their main putative bioactive compounds (polyphenols) using HPLC and LC-MS. CONCLUSION: The data demonstrated that guava leaf and fruit extracts can potentially contribute to the regulation of blood glucose levels.
Assuntos
Glucose/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Psidium/química , Animais , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Feminino , Frutas/química , Glucose/farmacocinética , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 5/genética , Transportador de Glucose Tipo 5/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos C57BL , Extratos Vegetais/análise , Extratos Vegetais/química , Folhas de Planta/química , Polifenóis/análise , Período Pós-Prandial , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismoRESUMO
Fructose is now such an important component of human diets, and several studies have found that some cancer cells could utilize fructose to overcome low glucose micro-environment, but the study on the role of fructose in glioma is rare. To explore the role of fructose in glioma, we detected the proliferation and colony formation ability of glioma cells in fructose medium, and found that the abilities of proliferation and colony formation of glioma cells in fructose medium were similar with abilities in glucose medium, however, fructose just partly restored proliferation ability of normal glial cells. To explore the mechanism, we compared the expression level of GLUT5 (Glucose transporter type 5) in these cell lines, and the results showed that glioma cell lines had higher GLUT5 expression than normal glial cell lines. And knockdown of GLUT5 could significantly inhabit cell proliferation of glioma cells in fructose medium. Furthermore, we found that GLUT5 was also higher expressed in glioma tissues, and GLUT5 expression correlated significantly with glioma malignancy and poor survival of glioma patients (pâ¯<â¯0.01). In addition, we also demonstrated that knockdown of GLUT5 could significantly inhabit tumor proliferation in vivo, and intake fructose could increase tumor volume prominently. Taken together, our data show that fructose can be used by glioma cells, and restrict the fructose intake or targeting GLUT5 could be efficacious strategies in glioma.
Assuntos
Progressão da Doença , Frutose/metabolismo , Glioma/patologia , Transportador de Glucose Tipo 5/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Glioma/genética , Glucose/deficiência , Transportador de Glucose Tipo 5/genética , Humanos , Masculino , Camundongos Nus , Microglia/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de SobrevidaRESUMO
Point-of-care applications rely on biomedical sensors to enable rapid detection with high sensitivity and selectivity. Despite advances in sensor development, there are challenges in cancer diagnostics. Detection of biomarkers, cell receptors, circulating tumor cells, gene identification, and fluorescent tagging are time-consuming due to the sample preparation and response time involved. Here, we present a novel approach to target the enhanced metabolism in breast cancers for rapid detection using fluorescent imaging. Fluorescent analogs of fructose target the fructose-specific transporter GLUT5 in breast cancers and have limited to no response from normal cells. These analogs demonstrate a marked difference in adenocarcinoma and premalignant cells leading to a novel detection approach. The vastly different uptake kinetics of the analogs yields two unique signatures for each cell type. We used normal breast cells MCF10A, adenocarcinoma cells MCF7, and premalignant cells MCF10AneoT, with hepatocellular carcinoma cells HepG2 as the negative control. Our data indicated that MCF10AneoT and MCF7 cells had an observable difference in response to only one of the analogs. The response, observed as fluorescence intensity, leads to a two-point assessment of the cells in any sample. Since the treatment time is 10 min, there is potential for use in rapid on-site high-throughput diagnostics.
Assuntos
Transporte Biológico/genética , Neoplasias da Mama/genética , Transportador de Glucose Tipo 5/genética , Sondas Moleculares/genética , Neoplasias da Mama/metabolismo , Feminino , HumanosRESUMO
Only limited data are available on the inhibition of the sugar transporter GLUT5 by flavonoids or other classes of bioactives. Intestinal GLUT7 is poorly characterised and no information exists concerning its inhibition. We aimed to study the expression of GLUT7 in Caco-2/TC7 intestinal cells, and evaluate inhibition of glucose transport by GLUT2 and GLUT7, and of fructose transport by GLUT2, GLUT5 and GLUT7, by flavonoids. Differentiated Caco-2/TC7 cell monolayers were used to investigate GLUT7 expression, as well as biotinylation and immunofluorescence to assess GLUT7 location. For mechanistic sugar transport studies, X. laevis oocytes were injected with individual mRNA, and GLUT protein expression on oocyte membranes was confirmed. Oocytes were incubated with D-[14C(U)]-glucose or D-[14C(U)]-fructose in the presence of flavonoids, and uptake was estimated by liquid scintilation counting. In differentiated Caco-2/TC7 cell monolayers, GLUT7 was mostly expressed apically. When applied apically, or to both compartments, sorbitol, galactose, L-glucose or sucrose did not affect GLUT7 mRNA expression. Fructose applied to both sides increased GLUT7 mRNA (13%, pâ¯≤â¯0.001) and total GLUT7 protein (2.7-fold, pâ¯≤â¯0.05), while the ratio between apical, basolateral and total GLUT7 protein was unchanged. In the X. laevis oocyte model, GLUT2-mediated glucose and fructose transport were inhibited by quercetin, (-)-epigallocatechin gallate (EGCG) and apigenin, GLUT5-mediated fructose transport was inhibited by apigenin and EGCG, but not by quercetin, and GLUT7-mediated uptake of both glucose and fructose was inhibited by apigenin, but not by quercetin nor EGCG. Expression of GLUT7 was increased by fructose, but only when applied to Caco-2/TC7 cells both apically and basolaterally. Since GLUT2, GLUT5 and GLUT7 show different patterns of inhibition by the tested flavonoids, we suggest that they have the potential to be used as investigational tools to distinguish sugar transporter activity in different biological settings.
Assuntos
Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Animais , Células CACO-2 , Frutose/metabolismo , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportador de Glucose Tipo 2/antagonistas & inibidores , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 5/antagonistas & inibidores , Transportador de Glucose Tipo 5/genética , Humanos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Xenopus laevisRESUMO
SCOPE: High glycaemic sugars result in blood-glucose spikes, while large doses of post-prandial fructose inundate the liver, causing an imbalance in energy metabolism, both leading to increased risk of metabolic malfunction and type 2 diabetes. Acarbose, used for diabetes management, reduces post-prandial hyperglycaemia by delaying carbohydrate digestion. METHODS AND RESULTS: Chamomile and green teas both inhibited digestive enzymes (α-amylase and maltase) related to intestinal sugar release, as already established for acarbose. However, acarbose had no effect on uptake of sugars using both differentiated human Caco-2 cell monolayers and Xenopus oocytes expressing human glucose transporter-2 (GLUT2) and GLUT5. Both teas effectively inhibited transport of fructose and glucose through GLUT2 inhibition, while chamomile tea also inhibited GLUT5. Long term incubation of Caco-2/TC7 cells with chamomile tea for 16 h or 4 days did not enhance the observed effects, indicating that inhibition is acute. Sucrase activity was directly inhibited by green tea and acarbose, but not chamomile. CONCLUSION: These findings show that chamomile and green teas are potential tools to manage absorption and metabolism of sugars with efficacy against high sugar bolus stress inflicted, for example, by high fructose syrups, where the drug acarbose would be ineffective.
Assuntos
Acarbose/farmacologia , Camomila/química , Glucose/metabolismo , Chá/química , Chás de Ervas , Animais , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Diferenciação Celular/efeitos dos fármacos , Frutose/metabolismo , Transportador de Glucose Tipo 2/antagonistas & inibidores , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 5/antagonistas & inibidores , Transportador de Glucose Tipo 5/genética , Transportador de Glucose Tipo 5/metabolismo , Humanos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Sacarose/metabolismo , Xenopus , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismoRESUMO
Human GLUT5 is a fructose-specific transporter in the glucose transporter family (GLUT, SLC2 gene family). Its substrate-specificity and tissue-specific expression make it a promising target for treatment of diabetes, metabolic syndrome and cancer, but few GLUT5 inhibitors are known. To identify and characterize potential GLUT5 ligands, we developed a whole-cell system based on a yeast strain deficient in fructose uptake, in which GLUT5 transport activity is associated with cell growth in fructose-based media or assayed by fructose uptake in whole cells. The former method is convenient for high-throughput screening of potential GLUT5 inhibitors and activators, while the latter enables detailed kinetic characterization of identified GLUT5 ligands. We show that functional expression of GLUT5 in yeast requires mutations at specific positions of the transporter sequence. The mutated proteins exhibit kinetic properties similar to the wild-type transporter and are inhibited by established GLUT5 inhibitors N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) and (-)-epicatechin-gallate (ECG). Thus, this system has the potential to greatly accelerate the discovery of compounds that modulate the fructose transport activity of GLUT5.