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

Shima,Takafumi; Taniguchi,Kohei; Tokumaru,Yoshihisa; Inomata,Yosuke; Arima,Jun; Lee,Sang-Woong; Takabe,Kazuaki; Yoshida,Kazuhiro; Uchiyama,Kazuhisa

doi:10.3892/or.2021.8218

January-2022 Volume 47 Issue 1

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January-2022 Volume 47 Issue 1

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Article Open Access

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

Authors:
- Takafumi Shima
- Kohei Taniguchi
- Yoshihisa Tokumaru
- Yosuke Inomata
- Jun Arima
- Sang-Woong Lee
- Kazuaki Takabe
- Kazuhiro Yoshida
- Kazuhisa Uchiyama
View Affiliations / Copyright

Affiliations: Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑8686, Japan, Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA, Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Gifu 501‑1194, Japan

Copyright: © Shima et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 7
|
Published online on: November 4, 2021

https://doi.org/10.3892/or.2021.8218
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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.

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

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