Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis

C. U. Lago; S. M. Nowinski; J. E. Rundhaug; M. E. Pfeiffer; K. Kiguchi; K. Hirasaka; X. Yang; E. M. Abramson; S. B. Bratton; O. Rho; R. Colavitti; M. A. Kenaston; T. Nikawa; C. Trempus; J. Digiovanni; S. M. Fischer; E. M. Mills

doi:10.1038/onc.2011.630

Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis

C. U. Lago, S. M. Nowinski, J. E. Rundhaug, M. E. Pfeiffer, K. Kiguchi, K. Hirasaka, X. Yang, E. M. Abramson, S. B. Bratton, O. Rho, R. Colavitti, M. A. Kenaston, T. Nikawa, C. Trempus, J. Digiovanni, S. M. Fischer, E. M. Mills

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	4725-4731
Number of pages	7
Journal	Oncogene
Volume	31
Issue number	44
DOIs	https://doi.org/10.1038/onc.2011.630
State	Published - Nov 1 2012
Externally published	Yes

Keywords

carcinogenesis
differentiation
mitochondria
skin
uncoupling proteins

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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10.1038/onc.2011.630

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Lago, C. U., Nowinski, S. M., Rundhaug, J. E., Pfeiffer, M. E., Kiguchi, K., Hirasaka, K., Yang, X., Abramson, E. M., Bratton, S. B., Rho, O., Colavitti, R., Kenaston, M. A., Nikawa, T., Trempus, C., Digiovanni, J., Fischer, S. M., & Mills, E. M. (2012). Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis. Oncogene, 31(44), 4725-4731. https://doi.org/10.1038/onc.2011.630

Lago, CU, Nowinski, SM, Rundhaug, JE, Pfeiffer, ME, Kiguchi, K, Hirasaka, K, Yang, X, Abramson, EM, Bratton, SB, Rho, O, Colavitti, R, Kenaston, MA, Nikawa, T, Trempus, C, Digiovanni, J, Fischer, SM & Mills, EM 2012, 'Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis', Oncogene, vol. 31, no. 44, pp. 4725-4731. https://doi.org/10.1038/onc.2011.630

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abstract = "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.",

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author = "Lago, {C. U.} and Nowinski, {S. M.} and Rundhaug, {J. E.} and Pfeiffer, {M. E.} and K. Kiguchi and K. Hirasaka and X. Yang and Abramson, {E. M.} and Bratton, {S. B.} and O. Rho and R. Colavitti and Kenaston, {M. A.} and T. Nikawa and C. Trempus and J. Digiovanni and Fischer, {S. M.} and Mills, {E. M.}",

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AU - Trempus, C.

AU - Digiovanni, J.

AU - Fischer, S. M.

AU - Mills, E. M.

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AB - 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.

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Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis

Abstract

Keywords

ASJC Scopus subject areas

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