title: Glycolytic ATP fuels the plasma membrane calcium pump critical for pancreatic cancer cell survival.
abstract: 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 Ca(2+) ([Ca(2+)]i), as the ATP-dependent plasma membrane Ca(2+) ATPase (PMCA) is critical for maintaining low [Ca(2+)]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, [Ca(2+)]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 [Ca(2+)]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.
authors.affiliation: From the Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, United Kingdom and.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: James
authors.forename: Anthony
authors.initials: A
authors.lastname: Chan
authors.forename: Oihane
authors.initials: O
authors.lastname: Erice
authors.forename: Ajith K
authors.initials: AK
authors.lastname: Siriwardena
authors.forename: Jason I E
authors.initials: JI
authors.lastname: Bruce
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000255:Adenosine Triphosphate / Q000172:deficiency / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology*
chemical_list: D027682:Cation Transport Proteins; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: ATP; Calcium ATPase; Calcium Overload; Calcium Signaling; Cell Death; Glycolysis; Metabolism; PMCA; Pancreatic Cancer; Warburg