Glucose addiction of cholangiocarcinoma: opportunities for therapeutic development

Abstract

The association between diabetes mellitus, hyperglycemia, and cholangiocarcinoma (CCA) development and progression has been established. One speculation of the effects of high glucose levels promoting CCA progression is via the feeding of substrate to the aerobic glycolysis or so-called Warburg effects in CCA cells. Several glycolytic enzymes and glucose transporters are upregulated in CCA and further activated by high glucose conditions. However, the increased glucose uptake and the increased aggressive phenotypes of CCA under high glucose conditions might not be solely due to this aberrant energy metabolism. High glucose conditions have been proven to be the activator of the other signaling pathways, as well as the precursors for dysregulated glycosylation of oncoproteins in CCA. The higher requirement of glucose and the abundant glucose availability in diabetic conditions then synergize to promote aggressive CCA phenotypes. Additionally, the glucose avidity could also become the Achilles heel of CCA cells, as they could be sensitive to glucose deprivation. The development of therapeutic agents targeting glucose metabolisms or glucose-activated pathways is promising for CCA treatments. This article reviews and discusses the up-to-date research on how high glucose is involved in CCA progression, both via Warburg effects and other mechanisms.

Keywords

Cholangiocarcinoma / diabetes mellitus / glycolysis / hyperglycemia / warburg effect

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