Premium
Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca 2+ ‐dependent death of cancer cells
Author(s) -
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
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201949117
Subject(s) - mitochondrion , hexokinase , cancer , membrane , cancer cell , displacement (psychology) , chemistry , microbiology and biotechnology , biochemistry , glycolysis , biology , metabolism , genetics , psychology , psychotherapist
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 Ca 2+ overload caused by Ca 2+ release from ER via inositol‐3‐phosphate receptors ( IP 3Rs) and by Ca 2+ entry through plasma membrane. This results in Ca 2+ ‐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.