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 Ca_v1.3 (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.

癌细胞增加葡萄糖代谢以支持有氧糖酵解。然而，仅某些癌细胞对葡萄糖戒断具有急性敏感性，而这种选择性敏感性的潜在机制尚不清楚。我们表明，葡萄糖剥夺在癌细胞中启动了依赖激酶RIPK1的细胞死亡途径。葡萄糖戒断触发了快速的质膜去极化，并且细胞外钙通过L型钙通道Ca _v流入细胞1.3（CACNA1D），然后激活激酶CAMK1。CAMK1和脱甲基酶PPME1是随后磷酸酶PP2A（PP2Ac）的催化亚基的脱甲基和失活以及RIPK1磷酸化所必需的。质膜去极化，去甲基化的PP2Ac和细胞死亡是由葡萄糖和防止，出乎意料的是，通过其代谢的模拟2-脱氧d -葡萄糖（2-DG），糖酵解抑制剂。这些发现揭示了葡萄糖作为信号分子的先前未知的功能，其保护细胞免受由质膜去极化诱导的死亡的影响，而与葡萄糖在糖酵解中的作用无关。该癌细胞死亡途径的成分代表针对癌症的潜在治疗靶标。