Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+-dependent death of cancer cells
Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+-dependent death of cancer cells
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DOI：
10.15252/embr.201949117
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发表时间：
2020-05-08
期刊：
影响因子：
7.7
通讯作者：
Rasola, Andrea
中科院分区：
文献类型：
--
作者：
Ciscato, Francesco;Filadi, Riccardo;Rasola, Andrea
癌细胞经历了代谢和生存途径的变化，从而增加了它们的恶性。糖酵解酶(HK2)的异构体2在许多肿瘤细胞类型中增强了葡萄糖代谢和对死亡刺激的抵抗力。在这里，我们观察到HK2位于线粒体-内质网(ER)接触部位，称为MAM(线粒体相关膜)。通过3-磷酸肌醇受体(IP3Rs)从内质网释放钙离子和通过质膜钙离子内流引起线粒体钙超载。这会导致钙依赖的钙蛋白酶激活、线粒体去极化和细胞死亡。HK2靶向多肽导致从患者新鲜分离的慢性淋巴细胞白血病B细胞的大量死亡，并且该多肽的一种可操作形式减少了在小鼠体内移植的乳腺癌和结肠癌细胞的生长，而不会对健康组织产生有害影响。这些结果确定了一条由HK2置换启动的信号通路，可以作为抗肿瘤策略激活。
Cancer cells undergo changes in metabolic and survival pathways that increase their malignancy. Isoform 2 of the glycolytic enzyme hexokinase (HK2) enhances both glucose metabolism and resistance to death stimuli in many neoplastic cell types. Here, we observe that HK2 locates at mitochondria-endoplasmic reticulum (ER) contact sites called MAMs (mitochondria-associated membranes). HK2 displacement from MAMs with a selective peptide triggers mitochondrial Ca2+ overload caused by Ca2+ release from ER via inositol-3-phosphate receptors (IP3Rs) and by Ca2+ entry through plasma membrane. This results in Ca2+-dependent calpain activation, mitochondrial depolarization and cell death. The HK2-targeting peptide causes massive death of chronic lymphocytic leukemia B cells freshly isolated from patients, and an actionable form of the peptide reduces growth of breast and colon cancer cells allografted in mice without noxious effects on healthy tissues. These results identify a signaling pathway primed by HK2 displacement from MAMs that can be activated as anti-neoplastic strategy.