Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is one of the bile duct cancers and a rare malignant tumor with a poor prognosis owing to a lack of early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is a treatment approach typically being attempted for the first line. However, its underlying mechanism of resistance to chemotherapy is poorly understood. We addressed this by studying the dynamics in the human ICC SCK cell line. Here, we report that the regulation of glucose and glutamine metabolism is a key factor in overcoming cisplatin resistance of SCK. Through RNA sequencing analysis, we discovered that the cell cycle-related gene set exhibits a high enrichment score in cisplatin-resistant SCK (SCK-R) cells rather than 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 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. Especially under glucose starvation, SCK-R cells are sensitized to cisplatin. Moreover, 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 suggests that a combination of GLUT inhibition, which mimics glucose starvation, and GLS1 inhibition could be a therapeutic strategy to increase the chemosensitivity of ICC.