title: The Plasma Membrane Calcium Pump in Pancreatic Cancer Cells Exhibiting the Warburg Effect Relies on Glycolytic ATP.
abstract: Evidence suggests that the plasma membrane Ca(2+)-ATPase (PMCA), which is critical for maintaining a low intracellular Ca(2+) concentration ([Ca(2+)]i), utilizes glycolytically derived ATP in pancreatic ductal adenocarcinoma (PDAC) and that inhibition of glycolysis in PDAC cell lines results in ATP depletion, PMCA inhibition, and an irreversible [Ca(2+)]i overload. We explored whether this is a specific weakness of highly glycolytic PDAC by shifting PDAC cell (MIA PaCa-2 and PANC-1) metabolism from a highly glycolytic phenotype toward mitochondrial metabolism and assessing the effects of mitochondrial versus glycolytic inhibitors on ATP depletion, PMCA inhibition, and [Ca(2+)]i overload. The highly glycolytic phenotype of these cells was first reversed by depriving MIA PaCa-2 and PANC-1 cells of glucose and supplementing with α-ketoisocaproate or galactose. These culture conditions resulted in a significant decrease in both glycolytic flux and proliferation rate, and conferred resistance to ATP depletion by glycolytic inhibition while sensitizing cells to mitochondrial inhibition. Moreover, in direct contrast to cells exhibiting a high glycolytic rate, glycolytic inhibition had no effect on PMCA activity and resting [Ca(2+)]i in α-ketoisocaproate- and galactose-cultured cells, suggesting that the glycolytic dependence of the PMCA is a specific vulnerability of PDAC cells exhibiting the Warburg phenotype.
authors: From the Faculty of Life Sciences.
authors: Andrew D
authors: AD
authors: James
authors: From the Faculty of Life Sciences.
authors: Waseema
authors: W
authors: Patel
authors: From the Faculty of Life Sciences.
authors: Zohra
authors: Z
authors: Butt
authors: From the Faculty of Life Sciences.
authors: Magretta
authors: M
authors: Adiamah
authors: From the Faculty of Life Sciences.
authors: Raga
authors: R
authors: Dakhel
authors: Manchester Pharmacy School, and.
authors: Ayse
authors: A
authors: Latif
authors: the Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Carolina
authors: C
authors: Uggenti
authors: From the Faculty of Life Sciences.
authors: Eileithyia
authors: E
authors: Swanton
authors: the Hakubi Center for Advanced Research and Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan, and.
authors: Hiromi
authors: H
authors: Imamura
authors: the Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Manchester M13 9NT, United Kingdom.
authors: Ajith K
authors: AK
authors: Siriwardena
authors: From the Faculty of Life Sciences, jason.bruce@manchester.ac.uk.
authors: Jason I E
authors: JI
authors: Bruce
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005690:Galactose / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019807:Iodoacetic Acid / Q000494:pharmacology; D007651:Keto Acids / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007651:Keto Acids; C013082:alpha-ketoisocaproic acid; D000255:Adenosine Triphosphate; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium; D019807:Iodoacetic Acid; D005690:Galactose
keywords: ATP; PMCA; Warburg effect; calcium; calcium ATPase; calcium overload; calcium pump; glycolysis; metabolism; pancreatic cancer