Uncoupling protein 2 (UCP2) is a mitochondrial protein present in the inner mitochondrial membrane. They belong to the family of anion mitochondrial carriers. UCP2 are thought to have natural antioxidant effect by attenuating the generation of superoxides.

Since cancer cells exhibit elevated oxidative stress, they can effectively adapt to this situation by upregulating UCP2. As a matter of fact, UCP2 is overexpressed in many forms of cancer including prostate, breast, lung and head & neck. Not surprising, our early studies demonstrate that knockout of UCP2 suppresses skin tumor formation in a multistage skin carcinogenesis model.

The purpose of this study was to detect the impact of UCP2's upregulation on mitochondrial redox status and mitochondrial respiration, using the well characterized tumor promotion model, JB6p+ cells. Our results have demonstrated that UCP2 overexpression enhanced protein expression and activity levels of manganese superoxide dismutase (MnSOD), a mitochondrial-resident enzyme that governs the egression of superoxides. To assess the impact of MnSOD upregulation on mitochondrial redox status, levels of superoxides and hydrogen peroxides were detected. Our results indicated that MnSOD upregulation maintained steady flow of hydrogen peroxides originating from mitochondria. We further examined the effect of UCP2 upregulation-induced MnSOD expression on mitochondrial respiration and glycolytic rate. In agreement with our data, cells overexpressing UCP2 had significantly higher oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). In conclusion, our data suggests that UCP2 promotes carcinogenesis via decreasing superoxide generation whereas promoting hydrogen peroxide production via elevating MnSOD. Collectively, our results support the hypothesis that enhanced UCP2 expression sustains metabolic switch in cancer cells.

Citation Format: Annapoorna Sreedhar, Yunfeng Zhao. The effect of UCP2 upregulation on cellular redox status and mitochondrial respiration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 216.