Cancer cells undergo changes in metabolic and survival pathways that increase their malignancy. Isoform 2 of the glycolytic enzyme hexokinase (HK 2) enhances both glucose metabolism and resistance to death stimuli in many neoplastic cell types. Here, we observe that HK 2 locates at mitochondria‐endoplasmic reticulum (ER ) contact sites called MAM s (mitochondria‐associated membranes). HK 2 displacement from MAM s with a selective peptide triggers mitochondrial Ca²⁺ overload caused by Ca²⁺ release from ER via inositol‐3‐phosphate receptors (IP 3Rs) and by Ca²⁺ entry through plasma membrane. This results in Ca²⁺‐dependent calpain activation, mitochondrial depolarization and cell death. The HK 2‐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 HK 2 displacement from MAM s that can be activated as anti‐neoplastic strategy.

中文翻译：

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己糖激酶 2 从线粒体相关膜上的置换促使癌细胞的 Ca2+ 依赖性死亡。

癌细胞的代谢和生存途径发生变化，从而增加了它们的恶性程度。糖酵解酶己糖激酶 (HK 2) 的异构体 2 可增强许多肿瘤细胞类型中的葡萄糖代谢和对死亡刺激的抵抗力。在这里，我们观察到 HK 2 位于称为 MAM s（线粒体相关膜）的线粒体-内质网 (ER) 接触位点。用选择性肽从 MAM s 置换 HK 2 会触发线粒体 Ca ²⁺过载，这是由ER 通过肌醇-3-磷酸受体 (IP 3Rs) 释放 Ca 2+ 和通过质膜进入 Ca ²⁺引起^的。这导致 Ca ²⁺依赖的钙蛋白酶激活、线粒体去极化和细胞死亡。HK 2 靶向肽会导致从患者身上新鲜分离的慢性淋巴细胞白血病 B 细胞大量死亡，并且该肽的一种可操作形式可减少小鼠同种异体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。这些结果确定了由 MAM 中的 HK 2 置换引发的信号通路，该通路可以作为抗肿瘤策略被激活。