The Plasma Membrane Calcium Pump in Pancreatic Cancer Cells Exhibiting the Warburg Effect Relies on Glycolytic ATP |
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Authors: | Andrew D James Waseema Patel Zohra Butt Magretta Adiamah Raga Dakhel Ayse Latif Carolina Uggenti Eileithyia Swanton Hiromi Imamura Ajith K Siriwardena Jason I E Bruce |
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Institution: | From the ‡Faculty of Life Sciences.;§Manchester Pharmacy School, and ;the ¶Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.;the ‖Hakubi Center for Advanced Research and Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan, and ;the **Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Manchester M13 9NT, United Kingdom |
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Abstract: | Evidence suggests that the plasma membrane Ca2+-ATPase (PMCA), which is critical for maintaining a low intracellular Ca2+ concentration (Ca2+]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 Ca2+]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 Ca2+]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 Ca2+]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. |
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Keywords: | ATP calcium calcium ATPase glycolysis metabolism pancreatic cancer Warburg effect PMCA calcium overload calcium pump |
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