The metabolic phenotype of pancreatic cancer: Effect on cytosolic Ca2+ signalling

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with even worse survival rates. Cancer cells are resistant to cell death due, in part, to a switch between mitochondrial and glycolytic metabolism (Warburg effect). In "normal" pancreatic exocrine cells the ATP-dependent plasma membrane Ca2+ pump (PMCA) maintains low resting cytosolic calcium ([Ca2+]i) which when inhibited can lead to cytosolic Ca2+ overload and cell death. Preliminary data show that restricting ATP supply to the PMCA, by inhibiting either the mitochondria or glycolysis, inhibits the PMCA in "normal" pancreatic exocrine cells. However, in pancreatic cancer cell lines (PANC1 and MiaPACA) the PMCA activity was resistant to mitochondrial inhibitors but sensitive to glycolytic inhibitors, suggesting that glycolytic ATP is critical for maintaining PMCA and presumably cell survival. This glycolytic regulation of the PMCA may be the “Achilles heel” of pancreatic cancer and thus targeting specific glycolytic pathways using selective inhibitors may therefore represent an effective therapeutic strategy for selectively killing cancer cells, while sparing healthy cells.

Hypothesis: The pro-survival phenotype is facilitated by a switch from mitochondrial to glycolytic metabolism which provides a rapid source of ATP to fuel the PMCA, maintain low [Ca2+]i and thus prevent cell death. This will be tested by attempting to artificially manipulate the relative contributions or sources of ATP to the PMCA using specific inhibitors of glycolytic enzymes and signalling pathways responsible for this metabolic switch.