Ca ²⁺ -dependent demethylation of phosphatase PP2Ac promotes glucose deprivation–induced cell death independently of inhibiting glycolysis

Abstract

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 Ca1.3 (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.

Akt‐mediated phosphorylation of MICU 1 regulates mitochondrial Ca 2+ levels and tumor growth

“…We aimed to identify putative patho‐physiological scenarios in which the MICU1 regulation by Akt could play an essential role. Glucose deprivation, a common form of metabolic stress, can induce Akt activation (Gao et al , ), and it has been recently showed that glucose withdrawal could regulate a series of molecular pathways by evoking Ca 2+ elevations (Lee et al , ). Thus, we investigated whether the Akt‐MICU1 signaling is involved in the cellular response to glucose starvation.…”

NADPH consumption by L-cystine reduction creates a metabolic vulnerability upon glucose deprivation

“…This glucose or glutamine "addiction" has been linked to signaling through AKT and AMPK [8][9][10] , mTORC1 11 , and tyrosine kinases 12 . Other studies have linked glucose deprivationinduced death to mechanisms independent of glycolysis including Ca 2+ influxes through the L-type calcium channel Cav1.3 13 and the glutamate/cystine antiporter xCT (SLC7A11) [14][15][16] . However, therapeutically targeting the glucose addiction phenotype remains a challenge 2 because 1) tumors cannot be completely starved of glucose in vivo;…”

“…For example, the glycolytic inhibitor 2-deoxyglucose (2-DG) demonstrates enhanced cytotoxicity when paired with BSO in human breast cancer cells55 or with antimycin A in human colon cancer cells20 . Interestingly, however, 2-DG supplementation can rescue cancer cells in the absence of glucose9,56 . This may be due to the fact that 2-DG can be metabolized in the pentose phosphate pathway 57 (PPP), thus allowing 2-DG to serve as an alternative source of NADPH when glucose is restricted.…”

Beyond Computational Genomics towards Systems Metabolomics for Precision Oncology

“…Glucose withdrawal causes rapid membrane depolarization and an influx of Ca 2+ , which activates a pathway given by kinase CAMK1 and demethylase PPME1. The following activation of PP2A promotes cell death (66). Besides glucose starvation is followed by an increase of the α-ketoglutarate to fumarate ratio, which favour PHD2 activation that promotes cell death by degrading B55, the inhibitory subunit of PP2A (67).…”

“…Of course it is necessary to fully understand the metabolic and bioenergetic responses that are generated, only in cancer cells, by glucose deprivation. Figure 5B presents a concept map of the signaling pathways, centered on mitochondrial PP2A, which have been recently regarded to control glucose deprivation-induced cancer cell death (66,67). Glucose withdrawal causes rapid membrane depolarization and an influx of Ca 2+ , which activates a pathway given by kinase CAMK1 and demethylase PPME1.…”