Mitochondrial HER2 stimulates respiration and promotes tumorigenicity
Autor
Magalhães-Novais, Sílvia
Dvořáková, Šárka
Dmytruk, Kristina
Zudová, Dagmar
Filimoněnko, Vlada
Procházka, Jan
Datum vydání
2024Publikováno v
European Journal of Clinical InvestigationRočník / Číslo vydání
54 (6)ISBN / ISSN
ISSN: 0014-2972ISBN / ISSN
eISSN: 1365-2362Metadata
Zobrazit celý záznamTato publikace má vydavatelskou verzi s DOI 10.1111/eci.14174
Abstrakt
Background: Amplification of HER2, a receptor tyrosine kinase and a breast cancer-linked oncogene, is associated with aggressive disease. HER2 protein is localised mostly at the cell membrane, but a fraction translocates to mitochondria. Whether and how mitochondrial HER2 contributes to tumorigenicity is currently unknown.Methods: We enriched the mitochondrial (mt-)HER2 fraction in breast cancer cells using an N-terminal mitochondrial targeting sequence and analysed how this manipulation impacts bioenergetics and tumorigenic properties. The role of the tyrosine kinase activity of mt-HER2 was assessed in wild type, kinase-dead (K753M) and kinase-enhanced (V659E) mtHER2 constructs.Results: We document that mt-HER2 associates with the oxidative phosphorylation system, stimulates bioenergetics and promotes larger respiratory supercomplexes. mt-HER2 enhances proliferation and invasiveness in vitro and tumour growth and metastatic potential in vivo, in a kinase activity-dependent manner. On the other hand, constitutively active mt-HER2 provokes excessive mitochondria ROS generation, sensitises to cell death, and restricts growth of primary tumours, suggesting that regulation of HER2 activity in mitochondria is required for the maximal pro-tumorigenic effect.Conclusions: mt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance.
Klíčová slova
cancer, electron transport chain, HER2, mitochondria, reactive oxygen species
Trvalý odkaz
https://hdl.handle.net/20.500.14178/2614Licence
Licence pro užití plného textu výsledku: Creative Commons Uveďte původ-Neužívejte dílo komerčně-Nezpracovávejte 4.0 International