Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca²⁺ -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

SUBMITTER: Ciscato F 

PROVIDER: S-EPMC7332982 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature