Abstract
Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead to glucose depletion. In the present study, we investigated how cholangiocarcinoma cells adapt to glucose depletion using a 3D organoid culture system. We cultured organoids derived from cholangiocarcinoma under glucose-free condition and investigated cell proliferation, expression of stem cell markers and resistance to gemcitabine. Cholangiocarcinoma organoids cultured under glucose-free condition showed reduced proliferation but were able to survive. We also observed an increase in the expression of stem cell markers including LGR5 and enhancement of stem cell phenotypic characteristics such as resistance to gemcitabine through AKT phosphorylation and reactive oxygen species. These findings indicate that cholangiocarcinoma cells are able to adapt to glucose depletion through enhancement of their stem cell phenotype in response to changes in microenvironmental conditions.
Highlights
Most cancer cells rely predominantly on anaerobic glycolysis to generate energy even under aerobic condition, a phenomenon known as the “Warburg effect” [1,2]
The human cholangiocarcinoma organoid lines CCO1 and CCO2 were cultured under two different conditions Glu (+) or Glu (−) for 14 days, and their growth activities were evaluated by counting viable cells
These results indicated that AKT phosphorylation and Reactive Oxygen Species (ROS) increased the stemness of cholangiocarcinoma organoids that had been initially cultured under glucose-sufficient condition and transferred to glucose-free condition
Summary
Most cancer cells rely predominantly on anaerobic glycolysis to generate energy even under aerobic condition, a phenomenon known as the “Warburg effect” [1,2]. Since glycolysis yields only two molecules of ATP, cancer cells require a large amount of glucose for energy production. It has been shown that the glucose concentration in colonic or gastric cancer tissue is only one tenth of that in normal tissue, whereas the concentration of lactate, the final product of glycolysis, is significantly elevated [3]. We have recently demonstrated that liver cancer cells can survive even under hypoglycemic condition through microRNA-mediated gene regulation [5]. Cholangiocarcinoma is a highly malignant adenocarcinoma originating from bile duct epithelial cells.
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