Abstract 1157: Potential mechanism for mitochondrial uncoupling protein 2 promotes skin carcinogenesis

Abstract

Abstract Mitochondrial uncoupling has recently been proposed as a novel survival mechanism for cancer cells, However, there is no direct evidence supporting that uncoupling proteins promote carcinogenesis. Herein, we examined whether mitochondrial uncoupling affects mouse skin carcinogenesis using uncoupling protein 2 (UCP2) homozygous knockout mice, and explored the mechanisms of tumor promotion by mitochondrial uncoupling by overexpressing UCP2 in JB6 P+ cells, which are the only characterized skin cell model to study tumor promotion. The vivo results indicate that the rates of oxygen consumption were only decreased in the carcinogen-treated UCP2 knockout mice whereas glycolysis was only increased in the carcinogen-treated wild-type mice. The levels of metabolites pyruvate, malate and succinate showed different trends after carcinogen treatments between the wild-type and UCP2 knockout mice. In addition, UCP2 knockout decreases 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2, especially on the regulation of the key enzyme in glycolysis), CyclinB1 and the oncoprotein Fra-1 expression during skin carcinogenesis. The vitro results indicate that overexpression of UCP2 enhanced colony formation in response to tumor promoter treatment. In addition, overexpression of UCP2 induced the upregulation of Fra-1 and PFKFB2 expression. Although UCP2 overexpression could suppress apoptosis in vitro, But UCP2 Knockout did not cause increase in apoptosis. This study provides the first in vivo evidence using UCP2 mice supporting that UCP2 promotes carcinogenesis. Although the current data are unable to answer the question of how UCP2 knockout suppresses skin cancer formation, an interesting and important finding is the adverse changes of the three metabolites and especially on the regulation of the key enzyme in glycolysis pathway during carcinogenesis, which provides a clue for future studies. Together with early studies showing that UCP2 is overexpressed in a number of human cancers and knockout of UCP2 significantly reduced the formation of both benign (papilloma) and malignant (squamous cell carcinoma) tumors in mice, UCP2 could be a potential target for cancer prevention and/or therapy. Citation Format: Chunjing Zhang, Yunfeng Zhao. Potential mechanism for mitochondrial uncoupling protein 2 promotes skin carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1157. doi:10.1158/1538-7445.AM2015-1157