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Glucose transporter-1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells

ABSTRACT: Imatinib mesylate (imatinib) is the primary agent of choice used to treat gastrointestinal stromal tumors (GIST). However, drug resistance to imatinib poses a major obstacle to treatment efficacy. In addition, the relationship between imatinib resistance and glycolysis is poorly understood. Glucose transporter (GLUT)-1 is a key component of glycolysis. The present study aimed to assess the potential relationship between components in the glycolytic pathway and the acquisition of imatinib resistance by GIST cells, with particular focus on GLUT-1. An imatinib-resistant GIST cell line was established through the gradual and continuous imatinib treatment of the parental human GIST cell line GIST-T1. The expression of glycolysis-related molecules (GLUT-1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) was assessed in parental and imatinib-resistant cells by western blotting, reverse transcription-quantitative PCR and glucose and lactate measurement kits. In addition, clinical information and transcriptomic data obtained from the gene expression omnibus database (GSE15966) were used to confirm the in vitro results. The potential effects of GLUT-1 inhibition on the expression of proteins in the glycolysis (GLUT-1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) and apoptosis pathways (Bcl-2, cleaved PARP, caspase-3 and caspase-9) in imatinib-resistant cells were then investigated following gene silencing and treatment using the GLUT-1 inhibitor WZB117 by western blotting. For gene silencing, the mature siRNAs for SLC2A1 were used for cell transfection. Annexin V-FITC/PI double-staining followed by flow cytometry was used to measure apoptosis whereas three-dimensional culture experiments were used to create three-dimensional spheroid cells where cell viability and spheroid diameter were measured. Although imatinib treatment downregulated GLUT-1 expression and other glycolysis pathway components hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase in parental GIST-T1 cells even at low concentrations. By contrast, expression of these glycolysis pathway components in imatinib-resistant cells were increased by imatinib treatment. WZB117 administration significantly downregulated AKT phosphorylation and Bcl-2 expression in imatinib-resistant cells, whereas the combined administration of imatinib and WZB117 conferred synergistic growth inhibition effects in apoptosis assay. WZB117 was found to exert additional inhibitory effects by inducing apoptosis in imatinib-resistant cells. Therefore, the present study suggests that GLUT-1 is involved in the acquisition of imatinib resistance by GIST cells, which can be overcome by combined treatment with WZB117 and imatinib.

SUBMITTER: Shima T

PROVIDER: S-EPMC8600406 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundType 2 diabetes mellitus has become one of the most important public health concerns worldwide. Due to its high prevalence and morbidity, there is an avid necessity to find new therapies that slow the progression and promote the regression of the disease. Imatinib mesylate is a tyrosine kinase inhibitor that binds to the Abelson tyrosine kinase and related proteins. It enhances β-cell survival in response to toxins and pro-inflammatory cytokine. The aim of this study is to evaluate the effect of imatinib on fasting plasma glucose in subjects with normal fasting glucose, subjects with impaired fasting glucose and in subjects with type 2 diabetes mellitus.MethodsWe identified 284 subjects diagnosed with chronic myeloid leukemia or gastrointestinal stromal tumors from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran database. 106/284 subjects were treated with imatinib. We compared the effect of imatinib on fasting plasma glucose after 1 and 6 months of treatment. We used ANOVA test of repeated samples to determine statistical significance in fasting plasma glucose before imatinib treatment and the follow-up. Statistical analysis was performed with Statistical Package for the Social Sciences v22.ResultsWe included a total of 106 subjects: 76 with fasting plasma glucose concentrations < 100 mg/dL (normal FG), 19 subjects with fasting plasma glucose concentrations ≥100 mg/dL (impaired fasting glucose), and 11 subjects with ≥126 mg/dL (type 2 diabetes mellitus). We found a significant increase in fasting plasma glucose concentration in the normal fasting glucose group (p = 0.048), and a significant decrease in fasting plasma glucose concentration in the type 2 diabetes mellitus group (p = 0.042). In the impaired fasting glucose group, we also found a tendency towards a decrease in fasting plasma glucose (p = 0.076). We identified 11 subjects with type 2 diabetes mellitus, of whom, 7 (64%) had a reduction in their fasting plasma glucose concentrations after 6 months. A significant glycosylated hemoglobin reduction (p = 0.04) was observed.ConclusionSubjects with chronic myeloid leukemia or gastrointestinal stromal tumor with type 2 diabetes mellitus had a significant reduction in fasting plasma glucose and glycosylated hemoglobin at 1 and 6 months while using imatinib.

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Glucose transporter-1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells

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