Prof I Bruce
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
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. Our previous studies 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 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.
Aims: This will be tested by identifying the specific glycolytic enzymes responsible for fuelling the PMCA and attempting inhibit this functional relationship to selectively kill pancreatic cancer cells.
Funding Notes
This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.
References
-James A, Chan A, Erice Azparren O, Siriwardena AJ, Bruce J.I.E. (2013). Glycolytic ATP Fuels the Plasma Membrane Calcium Pump Critical for Pancreatic Cancer Cell Survival. J. Biol Chem. 288(50):36007-19.
-Vander Heiden MG, Cantley LC, Thompson CB. (2009) Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science. 324(5930):1029-33.
-Cairns RA, Harris IS, Mak TW. (2011). Regulation of cancer cell metabolism. Nat Rev Cancer. 11(2):85-95.
-Kroemer G, Pouyssegur J. (2008). Tumor Cell Metabolism: Cancer’s Achilles’ Heel. Cancer Cell. 13(6):472-82.
-Tennant DA, Durán RV, Gottlieb E. (2010). Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 10(4):267-77.
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