Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 86, Issue -, Pages 67-77Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.04.032
Keywords
Oxidative stress; UCP2; ROS; Cancer; Cisplatin; Tamoxifen; Autophagic cell death; Resistance
Funding
- Fondo de Investigaciones Sanitarias of Instituto de Salud Carlos III of the Spanish Government [PI12/01827, PI14/01434]
- FEDER-Union Europea (Una manera de hacer Europa)
- Comunitat Autonoma de les Illes Balears
- FEDER [31/2011, AAEE22/2014]
- Comunidad Autonoma de las Islas Baleares
- Fondo Social Europeo
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Modulation of oxidative stress in cancer cells plays an important role in the study of the resistance to anticancer therapies. Uncoupling protein 2 (UCP2) may play a dual role in cancer, acting as a protective mechanism in normal cells, while its overexpression in cancer cells could confer resistance to chemotherapy and a higher survival through downregulation of ROS production. Thus, our aim was to check whether the inhibition of UCP2 expression and function increases oxidative stress and could render breast cancer cells more sensitive to cisplatin (CDDP) or tamoxifen (TAM). For this purpose, we studied clonogenicity, mitochondrial membrane potential (Delta Psi m), cell viability, ROS production, apoptosis, and autophagy in MCF-7 and T47D (only the last four deLerminaLions) breast cancer cells treated with CDDP or TAM, in combination or without a UCP2 knockdown (siRNA or genipin). Furthermore, survival curves were performed in order to check the impact, of UCP2 expression in breast cancer patients. UCP2 inhibition and cytotoxic treatments produced a decrease in cell viability and clonogenicity, in addition to an increase in Delta Psi m, ROS production, apoptosis, and autophagy. It is important to note that CDDP decreased UCP2 protein levels, so that the greatest areas produced by the UCP2 inhibition in combination with a cytotoxic treatment, with regard to treatment alone, were observed in TAM+UCP2siRNA-treated cells. Moreover, this UCP2 inhibition caused autophagic cell death, since apoptosis parameters barely increased after UCP2 knockdown. Finally, survival curves revealed that higher UCP2 expression corresponded with a poorer prognosis. In conclusion, UCP2 could be a therapeutic target in breast cancer, especially in those patients treated with tamoxilen. (C) 2015 Elsevier Inc. All rights reserved.
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