Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca2+‐dependent death of cancer cells. (8th May 2020)

• Record Type: Journal Article
• Authors: Ciscato, Francesco; Filadi, Riccardo; Masgras, Ionica; Pizzi, Marco; Marin, Oriano; Damiano, Nunzio; Pizzo, Paola; Gori, Alessandro; Frezzato, Federica; Chiara, Federica; Trentin, Livio; Bernardi, Paolo; Rasola, Andrea
• Is Part Of: EMBO reports. Volume 21:Number 7(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-05-08
• Subjects: anti‐neoplastic strategy -- cancer -- cell penetrating peptide -- Hexokinase 2 -- mitochondria‐associated membranes; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201949117
• Languages: English
• ISSNs: 1469-221X

Abstract

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 Ca 2+ overload caused by Ca 2+ release from ER via inositol‐3‐phosphate receptors (IP3Rs) and by Ca 2+ entry through plasma membrane. This results in Ca 2+ ‐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. Synopsis: Hexokinase 2 (HK2) localizes at mitochondria‐associated membranes (MAMs) of tumor cells. A cell‐penetrating peptide (HK2pep) dislodges HK2 from MAMs, prompts IP3R opening, mitochondria Ca 2+ overload, calpain activation and tumor cell death. An activatable HK2pep inhibits tumor growth in vivo . In tumor cells, the key metabolic enzyme Hexokinase 2 (HK2) localizes at endoplasmic reticulum‐mitochondria contact sites called MAMs (mitochondria‐associated membranes). HK2 displacement from MAMs with a cell‐penetrating peptide (HK2pep) elicits IP3R opening, mitochondrial Ca 2+ overload and calpain activation, rapidly killing tumor cells. An activatable HK2pep is suitable for in vivo delivery and inhibits tumor growth without noxious effects on healthy tissues. Abstract : HK2 localizes at mitochondria‐associated membranes of tumor cells. Its displacement with a cell‐penetrating peptide prompts IP3R opening, mitochondria Ca 2+ overload, calpain activation and tumor cell death.