Glycolytic ATP Fuels the Plasma Membrane Calcium Pump Critical for Pancreatic Cancer Cell Survival

• Published in: The Journal of biological chemistry Vol. 288; no. 50; pp. 36007 - 36019
• Main Authors: James, Andrew D., Chan, Anthony, Erice, Oihane, Siriwardena, Ajith K., Bruce, Jason I.E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.12.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Adenocarcinoma - pathology; Adenosine Triphosphate - deficiency; Adenosine Triphosphate - metabolism; ATP; Calcium - metabolism; Calcium ATPase; Calcium Overload; Calcium Signaling; Cation Transport Proteins - metabolism; Cell Death; Cell Line, Tumor; Cell Membrane - metabolism; Cell Survival; Cytosol - metabolism; Glycolysis; Humans; Metabolism; Mitochondria - metabolism; Pancreatic Cancer; Pancreatic Neoplasms - pathology; PMCA; Warburg; Cell Death; Calcium ATPase; Glycolysis; Warburg; Pancreatic Cancer; Metabolism; ATP; Calcium Signaling; PMCA; Calcium Overload
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.502948

Pancreatic cancer is an aggressive cancer with poor prognosis and limited treatment options. Cancer cells rapidly proliferate and are resistant to cell death due, in part, to a shift from mitochondrial metabolism to glycolysis. We hypothesized that this shift is important in regulating cytosolic Ca2+ ([Ca2+]i), as the ATP-dependent plasma membrane Ca2+ ATPase (PMCA) is critical for maintaining low [Ca2+]i and thus cell survival. The present study aimed to determine the relative contribution of mitochondrial versus glycolytic ATP in fuelling the PMCA in human pancreatic cancer cells. We report that glycolytic inhibition induced profound ATP depletion, PMCA inhibition, [Ca2+]i overload, and cell death in PANC1 and MIA PaCa-2 cells. Conversely, inhibition of mitochondrial metabolism had no effect, suggesting that glycolytic ATP is critical for [Ca2+]i homeostasis and thus survival. Targeting the glycolytic regulation of the PMCA may, therefore, be an effective strategy for selectively killing pancreatic cancer while sparing healthy cells. Background: Pancreatic cancer cells exhibit up-regulated glycolysis. Results: Inhibition of glycolysis, but not mitochondrial metabolism, induced ATP depletion, plasma membrane calcium pump (PMCA) inhibition, Ca2+ overload, and cell death. Conclusion: Glycolytic ATP fuels the PMCA in pancreatic cancer. Significance: Glycolytic regulation of the PMCA may represent a novel chemotherapeutic target for pancreatic cancer.