Abstract
To determine whether the differential growth inhibition of pancreatic tumor cells to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) correlates with uptake, expression of GLUT-1 transporter, and levels of hypoxic-inducible factor-1alpha.
Growth inhibition assays with 2-DG, lactic acid analysis, Western blots of GLUT-1, and hypoxic-inducible factor-1alpha were correlated with each other and with uptake and accumulation of radio-labeled 2-DG in 2 pancreatic cell lines.
Under normal oxygen tension, we find that the pancreatic cell line MIA PaCa2 (1420) is 7 times more sensitive to 2-DG and equally sensitive to oxamate, as compared with Panc-1 (1469). Lactate levels in both cell types are similarly low, indicating that mitochondria are functioning normally in these cells and that they are not solely dependent on glycolysis for survival under an aerobic microenvironment. Since oxamate does not use glucose transporters for entry into the cell, the equal sensitivity to this drug suggests that the selective growth inhibition of 2-DG in these 2 cell types might be reflective of differential expression of glucose transporters. Indeed, we find that GLUT-1 is more highly expressed in 1420 and that this cell line accumulates 2-DG twice as much as 1469. Additionally, hypoxic-inducible factor, which is known to upregulate the expression of GLUT-1, is found at equally low levels in both cell types. Thus, the increased expression of GLUT-1 in 1420 appears to be independent of hypoxia-inducible factor.
Overall, our results suggest that certain pancreatic tumors may be inherently sensitive to 2-DG, even under normal oxygen tension, due to greater intracellular accumulation of this inhibitor. Moreover, if 2-DG shows clinical efficacy, it may be possible to predict which pancreatic tumors would be sensitive to this agent based on their GLUT-1 expression profile and their increased uptake of 2-fluoro-deoxy-D-glucose currently used to image tumors via PET scanning.
