title: SIRT3 Silencing Sensitizes Breast Cancer Cells to Cytotoxic Treatments Through an Increment in ROS Production.
abstract: SIRT3, the major deacetylase in mitochondria, plays a crucial role modulating ROS production and scavenging by regulating key proteins implicated in mitochondrial turnover and in antioxidant defenses. Therefore, SIRT3 could confer resistance to chemotherapy-induced oxidative stress, leading to a lower ROS production and a higher cell survival. Our aim was to analyze whether SIRT3 silencing in breast cancer cells through a specific siRNA could increase oxidative stress and thus compromise the antioxidant response, resulting in a sensitization of the cells to cisplatin (CDDP) or tamoxifen (TAM). For this purpose, we studied cell viability, ROS production, apoptosis and autophagy in MCF-7 and T47D cell lines treated with these cytotoxic compounds, these either alone, or in combination with SIRT3 silencing. Moreover, protein levels regulated by SIRT3 were also examined and survival curves were analyzed to study the importance of SIRT3 expression for the overall survival of breast cancer patients. When SIRT3 was silenced and combined with cytotoxic treatments, cell viability was highly decreased, and was accompanied by a significant increase in ROS production. While TAM treatment increased autophagic cell death, CDDP significantly triggered apoptosis, whereas SIRT3 silencing produced an enhancement of these two action mechanisms. SIRT3 knockdown also affected PGC-1α and TFAM (mitochondrial biogenesis), and MnSOD and IDH2(antioxidant defenses) protein levels. Finally, survival curves showed that higher SIRT3 expression is correlated to a poorer prognosis for patients with grade 3 breast cancer. In conclusion, SIRT3 could be a therapeutic target for breast cancer, improving the effectiveness of CDDP and TAM treatments. J. Cell. Biochem. 118: 397-406, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain.|Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain.|Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, Edificio S. E-07120 Palma de Mallorca, Illes Balears, Spain.
authors.forename: Margalida
authors.initials: M
authors.lastname: Torrens-Mas
authors.affiliation: Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain.|Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain.|Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, Edificio S. E-07120 Palma de Mallorca, Illes Balears, Spain.
authors.forename: Daniel Gabriel
authors.initials: DG
authors.lastname: Pons
authors.affiliation: Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain.|Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain.|Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, Edificio S. E-07120 Palma de Mallorca, Illes Balears, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Sastre-Serra
authors.affiliation: Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain.|Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain.|Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, Edificio S. E-07120 Palma de Mallorca, Illes Balears, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Oliver
authors.affiliation: Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain.|Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain.|Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, Edificio S. E-07120 Palma de Mallorca, Illes Balears, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Roca
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056566:Sirtuin 3 / Q000096:biosynthesis*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D013629:Tamoxifen; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D002945:Cisplatin
keywords: BREAST CANCER; CISPLATIN; OXIDATIVE STRESS; SIRT3; TAMOXIFEN