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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma

  • So Mi Yang (Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University) ;
  • Jueun Kim (Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University) ;
  • Ji-Yeon Lee (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Jung-Shin Lee (Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University) ;
  • Ji Min Lee (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
  • Received : 2023.03.08
  • Accepted : 2023.07.03
  • Published : 2023.11.30
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Abstract

Intrahepatic cholangiocarcinoma (ICC) is a bile duct cancer and a rare malignant tumor with a poor prognosis owing to the lack of an early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is the typically attempted first-line treatment approach. However, the underlying mechanism of resistance to chemotherapy is poorly understood. We addressed this by studying dynamics in the human ICC SCK cell line. Here, we report that the regulation of glucose and glutamine metabolism was a key factor in overcoming cisplatin resistance in SCK cells. RNA sequencing analysis revealed a high enrichment cell cycle-related gene set score in cisplatin-resistant SCK (SCK-R) cells compared to parental SCK (SCK WT) cells. Cell cycle progression correlates with increased nutrient requirement and cancer proliferation or metastasis. Commonly, cancer cells are dependent upon glucose and glutamine availability for survival and proliferation. Indeed, we observed the increased expression of GLUT (glucose transporter), ASCT2 (glutamine transporter), and cancer progression markers in SCK-R cells. Thus, we inhibited enhanced metabolic reprogramming in SCK-R cells through nutrient starvation. SCK-R cells were sensitized to cisplatin, especially under glucose starvation. Glutaminase-1 (GLS1), which is a mitochondrial enzyme involved in tumorigenesis and progression in cancer cells, was upregulated in SCK-R cells. Targeting GLS1 with the GLS1 inhibitor CB-839 (telaglenastat) effectively reduced the expression of cancer progression markers. Taken together, our study results suggest that a combination of GLUT inhibition, which mimics glucose starvation, and GLS1 inhibition could be a therapeutic strategy to increase the chemosensitivity of ICC.

Keywords

Acknowledgement

This work was supported by the Basic Science Research Program NRF-2021R1C1C1008780 to J.M.L., 2020R1I1A3072234 to J-S.L., and 2021R1I1A1A01057137 to J.K. from the National Research Foundation (NRF) grant funded by the Korea government.

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