Abstract 439: Mitochondrial uncoupling protein 2 promotes skin carcinogenesis

Abstract

Abstract Mitochondrial uncoupling uncouples mitochondrial respiration and ATP production. There are five uncoupling proteins (UCPs), UCP2 is ubiquitous expressed and plays an important role in the reprogramming of cancer cell metabolism. However, little is known about at what stage of cancer development mitochondrial uncoupling occurs and what the role of UCP2 in cancer etiology. We will try to address these puzzles in present study. The well-established chemically-induced skin carcinogenesis mouse model was used and UCP2 wide-type (WT) and homozygous knockout (KO) mice were added to this study as direct evidence for the role of UCP2 during skin carcinogenesis. After forty-week treatment with chemical carcinogens, the incidence of papillomas in WT and KO TPA mice was 92.3% and 77.8%, respectively; and tumor multiplicity was 2.6 and 1.3, respectively. The incidence of carcinomas in WT and KO TPA treatment was 76.9% and 22.2%, respectively, and tumor multiplicity was 0.9 and 0.2, respectively. We next detected how the mitochondrial function and ATP generation would be changed in this model. UCP2 knockout slightly increased oxygen consumption compared with WT, whereas tumor promoter treatment suppressed oxygen consumption in both UCP2 KO and WT group. As for ATP generation, there was no significant change between WT and KO, or between vehicle and tumor promoter treatment. We next examined 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. Anchorage-independent growth assay was performed and the results showed that overexpression of UCP2 enhanced colony formation in response to tumor promoter treatment. In addition, overexpression of UCP2 induced the upregulation of the oncoprotein Fra-1 whereas inhibited the increase in p53 expression. In summary, this study will add new knowledge to the understanding of the role of mitochondrial uncoupling in cancer etiology, and many help design a mitochondrial uncoupling-targeted approach for the suppression of cancer development. Citation Format: Wenjuan Li, Chunjing Zhang, Runhua Shi, Xin Gu, Yunfeng Zhao. Mitochondrial uncoupling protein 2 promotes skin carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 439. doi:10.1158/1538-7445.AM2014-439