Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca 2+ -dependent death of cancer cells
Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca 2+ -dependent death of cancer cells
Abstract 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 signalling pathway primed by HK2 displacement from MAMs that can be activated as anti-neoplastic strategy.
Ciscato Francesco、Masgras Ionica、Damiano Nunzio、Pizzo Paola、Gori Alessandro、Filadi Riccardo、Marin Oriano、Trentin Livio、Pizzi Marco、Bernardi Paolo、Frezzato Federica、Rasola Andrea
Department of Biomedical Sciences (DSB), University of PadovaDepartment of Biomedical Sciences (DSB), University of PadovaDepartment of Biomedical Sciences (DSB), University of PadovaDepartment of Biomedical Sciences (DSB), University of PadovaCNR Institute of Chemistry of Molecular Recognition (ICRM)Department of Biomedical Sciences (DSB), University of PadovaDepartment of Biomedical Sciences (DSB), University of PadovaHematology and Clinical Immunology Branch, Department of Medicine (DIMED), University of PadovaSurgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of PadovaDepartment of Biomedical Sciences (DSB), University of PadovaHematology and Clinical Immunology Branch, Department of Medicine (DIMED), University of PadovaDepartment of Biomedical Sciences (DSB), University of Padova
基础医学肿瘤学生物化学
Anti-neoplastic strategycancercell penetrating peptideHexokinase 2mitochondria-associated membranes
Ciscato Francesco,Masgras Ionica,Damiano Nunzio,Pizzo Paola,Gori Alessandro,Filadi Riccardo,Marin Oriano,Trentin Livio,Pizzi Marco,Bernardi Paolo,Frezzato Federica,Rasola Andrea.Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca 2+ -dependent death of cancer cells[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/736538.点此复制
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