0585963 - BTÚ 2025 RIV US eng J - Článek v odborném periodiku
Novotná, Eliška - Miloševič, Mirko - Průková, Dana - Magalhaes-Novais, Silvia - Dvořáková, Šárka - Dmytruk, Kristina - Gemperle, J. - Zudová, Dagmar - Nickl, Tereza - Vrbacký, Marek - Rosel, D. - Filimonenko, Vlada - Procházka, Jan - Brabek, J. - Neužil, Jiří - Rohlenová, Kateřina - Rohlena, Jakub
Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.
European Journal of Clinical Investigation. Roč. 54, č. 6 (2024). ISSN 0014-2972. E-ISSN 1365-2362
Grant CEP: GA ČR(CZ) GA22-34507S; GA ČR(CZ) GX21-04607X; GA MZd(CZ) NU23-03-00226; GA MŠMT LX22NPO5102; GA MŠMT LM2023036; GA MŠMT(CZ) EF18_046/0016045; GA MŠMT(CZ) EF16_013/0001775; GA MŠMT(CZ) LM2023050
Institucionální podpora: RVO:86652036 ; RVO:67985823 ; RVO:68378050
Klíčová slova: cancerelectron transport chain * HER2 * electron transport chain * mitochondria
Obor OECD: Cell biology
Impakt faktor: 4.4, rok: 2023 ; AIS: 1.25, rok: 2023
Způsob publikování: Open access
Web výsledku:
https://onlinelibrary.wiley.com/doi/10.1111/eci.14174DOI: https://doi.org/10.1111/eci.14174

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.
Trvalý link: https://hdl.handle.net/11104/0354523