The plasma membrane calcium pump in pancreatic cancer cells exhibiting the warburg effect relies on glycolytic ATP

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

    Research output: Contribution to journalArticlepeer-review

    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.
    Original languageEnglish
    Pages (from-to)24747-24759
    Number of pages13
    JournalThe Journal of biological chemistry
    Volume290
    Issue number41
    DOIs
    Publication statusPublished - 9 Oct 2015

    Keywords

    • ATP
    • PMCA
    • Warburg effect
    • calcium
    • calcium ATPase
    • calcium overload
    • calcium pump
    • glycolysis
    • metabolism
    • pancreatic cancer

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