Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+ -dependent death of cancer cells.
EMBO Rep
; 21(7): e49117, 2020 07 03.
Article
in En
| MEDLINE
| ID: mdl-32383545
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 signaling pathway primed by HK2 displacement from MAMs that can be activated as anti-neoplastic strategy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hexokinase
/
Neoplasms
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
EMBO Rep
Journal subject:
BIOLOGIA MOLECULAR
Year:
2020
Document type:
Article
Affiliation country: