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Eur J Clin Invest ; 54(6): e14174, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38291340

ABSTRACT

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.


Subject(s)
Breast Neoplasms , Mitochondria , Receptor, ErbB-2 , Mitochondria/metabolism , Humans , Receptor, ErbB-2/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Female , Animals , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Mice , Carcinogenesis/metabolism , Oxidative Phosphorylation , Cell Proliferation , Energy Metabolism , Cell Respiration/physiology
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