Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis
| Autor: | Edward M. Mills, Katsuya Hirasaka, Kaoru Kiguchi, John DiGiovanni, Joyce E. Rundhaug, X.L. Yang, Okkyung Rho, Ellen M. Abramson, Matthew Pfeiffer, Shawn B. Bratton, Takeshi Nikawa, C. U. Lago, Sara M. Nowinski, Carol S. Trempus, Renata Colavitti, Susan M. Fischer, M. A. Kenaston |
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| Rok vydání: | 2012 |
| Předmět: |
Keratinocytes
Cancer Research Cellular differentiation Transgene Gene Expression Biology Mitochondrion medicine.disease_cause Resting Phase Cell Cycle Article Ion Channels Mitochondrial Proteins Mice chemistry.chemical_compound Oxygen Consumption Genetics medicine Animals Uncoupling Protein 3 Molecular Biology Skin integumentary system Stem Cells Wild type Cell Differentiation Mitochondria Cell biology Cell Transformation Neoplastic medicine.anatomical_structure chemistry Epidermis Stem cell Carcinogenesis Keratinocyte Bromodeoxyuridine |
| Zdroj: | Oncogene. 31:4725-4731 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2011.630 |
| Popis: | Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment. |
| Databáze: | OpenAIRE |
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