Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma
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Intrahepatic cholangiocarcinoma (ICC) is a bile duct cancer anda rare malignant tumor with a poor prognosis owing to thelack of an early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is thetypically attempted first-line treatment approach. However, theunderlying mechanism of resistance to chemotherapy is poorlyunderstood. We addressed this by studying dynamics in thehuman ICC SCK cell line. Here, we report that the regulationof glucose and glutamine metabolism was a key factor in overcomingcisplatin resistance in SCK cells. RNA sequencinganalysis revealed a high enrichment cell cycle-related gene setscore in cisplatin-resistant SCK (SCK-R) cells compared to parentalSCK (SCK WT) cells. Cell cycle progression correlateswith increased nutrient requirement and cancer proliferationor metastasis. Commonly, cancer cells are dependent uponglucose and glutamine availability for survival and proliferation. Indeed, we observed the increased expression of GLUT(glucose transporter), ASCT2 (glutamine transporter), and cancerprogression markers in SCK-R cells. Thus, we inhibited enhancedmetabolic reprogramming in SCK-R cells through nutrient starvation. SCK-R cells were sensitized to cisplatin, especially underglucose starvation. Glutaminase-1 (GLS1), which is a mitochondrialenzyme involved in tumorigenesis and progression incancer cells, was upregulated in SCK-R cells. Targeting GLS1with the GLS1 inhibitor CB-839 (telaglenastat) effectively reducedthe expression of cancer progression markers. Takentogether, our study results suggest that a combination of GLUTinhibition, which mimics glucose starvation, and GLS1 inhibitioncould be a therapeutic strategy to increase the chemosensitivityof ICC.
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a bile duct cancer anda rare malignant tumor with a poor prognosis owing to thelack of an early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is thetypically attempted first-line treatment approach. However, theunderlying mechanism of resistance to chemotherapy is poorlyunderstood. We addressed this by studying dynamics in thehuman ICC SCK cell line. Here, we report that the regulationof glucose and glutamine metabolism was a key factor in overcomingcisplatin resistance in SCK cells. RNA sequencinganalysis revealed a high enrichment cell cycle-related gene setscore in cisplatin-resistant SCK (SCK-R) cells compared to parentalSCK (SCK WT) cells. Cell cycle progression correlateswith increased nutrient requirement and cancer proliferationor metastasis. Commonly, cancer cells are dependent uponglucose and glutamine availability for survival and proliferation. Indeed, we observed the increased expression of GLUT(glucose transporter), ASCT2 (glutamine transporter), and cancerprogression markers in SCK-R cells. Thus, we inhibited enhancedmetabolic reprogramming in SCK-R cells through nutrient starvation. SCK-R cells were sensitized to cisplatin, especially underglucose starvation. Glutaminase-1 (GLS1), which is a mitochondrialenzyme involved in tumorigenesis and progression incancer cells, was upregulated in SCK-R cells. Targeting GLS1with the GLS1 inhibitor CB-839 (telaglenastat) effectively reducedthe expression of cancer progression markers. Takentogether, our study results suggest that a combination of GLUTinhibition, which mimics glucose starvation, and GLS1 inhibitioncould be a therapeutic strategy to increase the chemosensitivityof ICC.
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