Research ArticleCell death

Ca2+-dependent demethylation of phosphatase PP2Ac promotes glucose deprivation–induced cell death independently of inhibiting glycolysis

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Sci. Signal.  09 Jan 2018:
Vol. 11, Issue 512, eaam7893
DOI: 10.1126/scisignal.aam7893

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A glucose-calcium connection in cell death

Glucose is a critical nutrient for cell survival, particularly in neurons and some types of cancer cells. Lee et al. found that some cancer cells are particularly sensitive to glucose loss but not because of starvation as one might expect. Loss of glucose triggered the influx of calcium across the plasma membrane, which activated a protein that demethylated (and inactivated) the phosphatase PP2A, leading to cell death through the activity of the kinase RIPK1. RIPK1 triggered cell death through a pathway that is unlike the currently recognized apoptosis, necroptosis, and necrosis mechanisms. A nonmetabolizable analog of glucose did not promote, but rather prevented, cell death by inhibiting cell membrane depolarization, hence blocking calcium influx. This knowledge might be used to therapeutically induce cell death in tumors or perhaps even prevent cell death in other cell types, such as neurons.


Cancer cells increase glucose metabolism to support aerobic glycolysis. However, only some cancer cells are acutely sensitive to glucose withdrawal, and the underlying mechanism of this selective sensitivity is unclear. We showed that glucose deprivation initiates a cell death pathway in cancer cells that is dependent on the kinase RIPK1. Glucose withdrawal triggered rapid plasma membrane depolarization and an influx of extracellular calcium into the cell through the L-type calcium channel Cav1.3 (CACNA1D), followed by activation of the kinase CAMK1. CAMK1 and the demethylase PPME1 were required for the subsequent demethylation and inactivation of the catalytic subunit of the phosphatase PP2A (PP2Ac) and the phosphorylation of RIPK1. Plasma membrane depolarization, PP2Ac demethylation, and cell death were prevented by glucose and, unexpectedly, by its nonmetabolizable analog 2-deoxy-d-glucose (2-DG), a glycolytic inhibitor. These findings reveal a previously unknown function of glucose as a signaling molecule that protects cells from death induced by plasma membrane depolarization, independently of its role in glycolysis. Components of this cancer cell death pathway represent potential therapeutic targets against cancer.

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