Mitochondrial uncoupling (uncouples electron transport from ATP production) has recently been proposed as a novel survival mechanism for cancer cells, and reduction in free radical generation is the accepted mechanism of action. 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 and wild-type mice. The results indicate that knockout of Ucp2 significantly reduced the formation of both benign (papilloma) and malignant (squamous cell carcinoma) tumors. UCP2 knockout did not cause increases in apoptosis during skin carcinogenesis. The rates of oxygen consumption were decreased only in the carcinogen-treated UCP2 knockout mice, whereas glycolysis was increased only in the carcinogen-treated wild-type mice. Finally, the levels of metabolites pyruvate, malate, and succinate showed different trends after carcinogen treatments between the wild-type and UCP2 knockout mice. Our study is the first to demonstrate that Ucp2 knockout suppresses carcinogenesis in vivo. Together with early studies showing that UCP2 is overexpressed in a number of human cancers, UCP2 could be a potential target for cancer prevention and/or therapy. Cancer Prev Res; 8(6); 487-91. ©2015 AACR.
©2015 American Association for Cancer Research.