Abstract 5425: Epidermal respiratory uncoupling blocks skin carcinogenesis by inhibiting Akt.

Abstract

Abstract Metabolic reprogramming, characterized by increased glycolysis and decreased oxygen consumption, is now considered a hallmark of malignancy. Mitochondrial uncoupling proteins oppose this phenotype by driving futile mitochondrial respiration that is uncoupled from ATP synthesis, and mice expressing a keratin 5 - uncoupling protein 3 (K5-UCP3) transgene in the epidermis are completely protected from the formation of chemically induced skin carcinomas. We crossed these mice with Tg.AC mice that express a cutaneous oncogenic v-Ha-Ras transgene, bypassing tumor initiation. Bi-transgenic Tg.AC/K5-UCP3 mice were still remarkably resistant to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumorigenesis, indicating that UCP3 likely inhibits tumor promotion. Accordingly, K5-UCP3 mice exhibited striking resistance to epidermal proliferation induced by TPA as measured using a bromodeoxyuridine (BrdU) based labeling assay. In agreement with these data, K5-UCP3 epidermis failed to show activation of Akt (Ser473 & Thr308 phosphorylation) and phosphorylation of downstream signaling molecules in response to TPA treatment. This effect corresponded to decreased expression of cyclins D1 and A, and increased expression of the cell cycle inhibitory proteins p21 and p27. Decreased Akt activation was also observed in vitro in response to epidermal growth factor (EGF) treatment of serum starved, isolated K5-UCP3 primary keratinocytes. To test the notion that the lack of Akt signaling was responsible for the lack of TPA induced proliferation and tumorigenesis, we bred bi-transgenic K5-UCP3/K5-Akt mice, and found that over-expression of wild type Akt recovered proliferation following TPA treatment. Future experiments will elucidate the mechanism underlying UCP3-induced inhibition of Akt activation and signaling. Citation Format: Sara M. Nowinski, Joyce E. Rundhaug, Okkyung Rho, Cory U. Lago, Susan M. Fischer, John DiGiovanni, Edward M. Mills. Epidermal respiratory uncoupling blocks skin carcinogenesis by inhibiting Akt. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5425. doi:10.1158/1538-7445.AM2013-5425