Triiodothyronine promotes the proliferation and chemoresistance of cholangiocarcinoma cells via HIF-1α/Glut1-stimulated glycolysis

Thyroid hormones not only are crucial for normal growth, development, and metabolism but also influence the development and progression of various malignancies. The effects of thyroid hormones on cholangiocarcinoma remain unclear. Here, we examined the effects of triiodothyronine (T3), a major thyroid hormone, on the behavior of cultured human cholangiocarcinoma cells after short-term (1 week) or long-term (6 months) T3 treatment. Whereas short-term T3 treatment did not influence the growth or behavior of cholangiocarcinoma cells, long-term T3 treatment had several significant effects. Cell proliferation, colony-forming and spheroid formation assays indicated the long-term T3 treatment increased cholangiocarcinoma cell growth in vitro and in mouse xenografts, and increased resistance to gemcitabine and cisplatin. Cells exposed to T3 long-term also exhibited increased glycolysis in a manner dependent on the glucose transporter 1 (Glut1). Expression of both Glut1 and hypoxia-inducible transcription factor 1α (HIF-1α) was upregulated in long-term T3-treated cholangiocarcinoma cells. Either pharmacological inhibition of Glut1 activity or siRNA-mediated knockdown of HIF-1α expression suppressed the increase in proliferation and chemoresistance induced by long-term T3 treatment. Notably, HIF-1α knockdown also reversed the effects of T3 exposure on Glut1 expression and glycolytic rate. Moreover, inhibition of lactate dehydrogenase suppressed upregulated expression of HIF-1α in long-term T3-treated cells. Finally, we found that elevated T3 levels activated the HIF-1α/Glut1 axis in ICC tissues and was associated with a worse prognosis of ICC patients. These results demonstrate that chronic exposure to T3 can promote the proliferation and chemoresistance of cholangiocarcinoma cells through a pathway involving HIF-1α, Glut1, and glycolysis.