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Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells
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‐endopl...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332982/ https://www.ncbi.nlm.nih.gov/pubmed/32383545 http://dx.doi.org/10.15252/embr.201949117 |
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author | 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 |
author_facet | 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 |
author_sort | Ciscato, Francesco |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7332982 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73329822020-07-07 Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells 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 EMBO Rep Reports 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. John Wiley and Sons Inc. 2020-05-08 2020-07-03 /pmc/articles/PMC7332982/ /pubmed/32383545 http://dx.doi.org/10.15252/embr.201949117 Text en © 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Reports 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 Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells |
title | Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells |
title_full | Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells |
title_fullStr | Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells |
title_full_unstemmed | Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells |
title_short | Hexokinase 2 displacement from mitochondria‐associated membranes prompts Ca(2+)‐dependent death of cancer cells |
title_sort | hexokinase 2 displacement from mitochondria‐associated membranes prompts ca(2+)‐dependent death of cancer cells |
topic | Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332982/ https://www.ncbi.nlm.nih.gov/pubmed/32383545 http://dx.doi.org/10.15252/embr.201949117 |
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