Kristiansen 2011 J Biol Chem
|Kristiansen G, Hu J, Wichmann D, Stiehl DP, Rose M, Gerhardt J, Bohnert A, ten Haaf A, Moch H, Raleigh J, Varia MA, Subarsky P, Scandurra FM, Gnaiger E, Gleixner E, Bicker A, Gassmann M, Hankeln T, Dahl E, Gorr TA (2011) Endogenous myoglobin in breast cancer is hypoxia-inducible by alternate transcription and functions to impair mitochondrial activity: a role in tumor suppression? J Biol Chem 286:43417-28.|
Kristiansen G, Hu J, Wichmann D, Stiehl DP, Rose M, Gerhardt J, Bohnert A, ten Haaf A, Moch H, Raleigh J, Varia MA, Subarsky P, Scandurra FM, Gnaiger E, Gleixner E, Bicker A, Gassmann M, Hankeln T, Dahl E, Gorr TA (2011) J Biol Chem
Abstract: O2k-in brief
Recently, immunohistochemical analysis of myoglobin (MB) in human breast cancer specimens has revealed a surprisingly widespread expression of MB in this non-muscle context. The positive correlation with hypoxia-inducible factor 2 (HIF-2α) and carbonic anhydrase IX suggested that oxygen regulates myoglobin expression in breast carcinomas. Here we report that MB mRNA and protein levels are robustly induced by prolonged hypoxia in breast cancer cell lines, in part via HIF-1/-2 dependent transactivation. The hypoxia-induced MB mRNA originated from a novel, alternative transcription start site 6 kb upstream of the ATG codon. MB regulation in normal and tumor tissue may thus be fundamentally different.
Functionally, the knockdown of MB in MDAMB468 breast cancer cells resulted in an unexpected increase of O2 uptake and elevated activities of mitochondrial enzymes during hypoxia. Silencing of MB transcription attenuated proliferation rates and motility capacities of hypoxic and, surprisingly, also fully oxygenated breast cancer cells. Endogenous MB in cancer cells is apparently involved in controlling oxidative cell energy metabolism, contrary to the mouse heart, where the targeted disruption of the Mb gene did not effect myocardial energetics and O2 consumption (1). This control function of MB seemingly impacts mitochondria and influences cell proliferation and motility, but it does so in ways not directly related to the facilitated diffusion or storage of O2. Hypothetically, MB´s mitochondria-impairing role in hypoxic cancer cells is part of a novel tumor-suppressive function.
• Keywords: breast cancer, myoglobin, hypoxia, gene regulation, respirometry
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Genetic knockout;overexpression, mt-Medicine Pathology: Cancer
Organism: Human Tissue;cell: Genital, Other cell lines Preparation: Intact cells
Regulation: Aerobic glycolysis, Oxygen kinetics, Substrate Coupling state: ROUTINE
- Contribution from the K-Regio project MitoCom Tyrol.