Endogenous Myoglobin in Breast Cancer Is Hypoxia-inducible by Alternative Transcription and Functions to Impair Mitochondrial Activity
Autor: | James A. Raleigh, Mahesh A. Varia, Josefine Gerhardt, Eva Gleixner, Daniel P. Stiehl, Patrick Subarsky, Francesca M. Scandurra, Max Gassmann, Michael Rose, Annette Bohnert, Annette Ten Haaf, Daniela Wichmann, Glen Kristiansen, Thomas Hankeln, Junmin Hu, Holger Moch, Thomas A. Gorr, Erich Gnaiger, Edgar Dahl, Anne Bicker |
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Rok vydání: | 2011 |
Předmět: |
0303 health sciences
Gene knockdown Tumor suppressor gene Cell growth Cell Cell Biology Biology Mitochondrion Biochemistry Molecular biology 03 medical and health sciences Transactivation 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer cell medicine Cancer research Gene silencing Molecular Biology 030304 developmental biology |
Zdroj: | Journal of Biological Chemistry. 286:43417-43428 |
ISSN: | 0021-9258 |
DOI: | 10.1074/jbc.m111.227553 |
Popis: | Recently, immunohistochemical analysis of myoglobin (MB) in human breast cancer specimens has revealed a surprisingly widespread expression of MB in this nonmuscle context. The positive correlation with hypoxia-inducible factor 2α (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 MDA-MB468 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 cancer cells and, surprisingly, also fully oxygenated breast cancer cells. Endogenous MB in cancer cells is apparently involved in controlling oxidative cell energy metabolism, contrary to earlier findings on mouse heart, where the targeted disruption of the Mb gene did not effect myocardial energetics and O2 consumption. 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, the mitochondrion-impairing role of MB in hypoxic cancer cells is part of a novel tumor-suppressive function. |
Databáze: | OpenAIRE |
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