Glucose transporter1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells.
Oncol Rep
; 47(1)2022 Jan.
Article
en En
| MEDLINE
| ID: mdl-34738628
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 GLUT1. An imatinibresistant GIST cell line was established through the gradual and continuous imatinib treatment of the parental human GIST cell line GISTT1. The expression of glycolysisrelated molecules (GLUT1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) was assessed in parental and imatinibresistant cells by western blotting, reverse transcriptionquantitative 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 GLUT1 inhibition on the expression of proteins in the glycolysis (GLUT1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) and apoptosis pathways (Bcl2, cleaved PARP, caspase-3 and caspase-9) in imatinibresistant cells were then investigated following gene silencing and treatment using the GLUT1 inhibitor WZB117 by western blotting. For gene silencing, the mature siRNAs for SLC2A1 were used for cell transfection. Annexin VFITC/PI doublestaining followed by flow cytometry was used to measure apoptosis whereas threedimensional culture experiments were used to create threedimensional spheroid cells where cell viability and spheroid diameter were measured. Although imatinib treatment downregulated GLUT1 expression and other glycolysis pathway components hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase in parental GISTT1 cells even at low concentrations. By contrast, expression of these glycolysis pathway components in imatinibresistant cells were increased by imatinib treatment. WZB117 administration significantly downregulated AKT phosphorylation and Bcl2 expression in imatinibresistant 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 imatinibresistant cells. Therefore, the present study suggests that GLUT1 is involved in the acquisition of imatinib resistance by GIST cells, which can be overcome by combined treatment with WZB117 and imatinib.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Resistencia a Antineoplásicos
/
Tumores del Estroma Gastrointestinal
/
Transportador de Glucosa de Tipo 1
/
Mesilato de Imatinib
/
Neoplasias Gastrointestinales
/
Hidroxibenzoatos
Límite:
Humans
Idioma:
En
Revista:
Oncol Rep
Asunto de la revista:
NEOPLASIAS
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón