engleski

De novo expression of transfected Sirt3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment

Oxidative stress and high levels of reactive oxygen species cause DNA damage and genomic instability, thus leading to changes in cell metabolism and loss of the cell cycle control. Sirtuin 3 (Sirt3) is the major mitochondrial NAD+-dependent deacetylase which keeps the cell in energetic homeostasis. Sirt3 has a promising role in cancer tumorigenesis and treatment, but there have been controversies about its role as oncogene or tumor suppressor in different types of cancer. Changes in its expression are associated with the excessive production of reactive oxygen species (ROS), thus contributing to mitochondrial dysfunction and age-related pathologies. Hyperoxic treatment (i.e. generator of ROS) was shown to support some tumorigenic properties, but finally suppresses growth of certain mammary carcinoma cells. Due to strikingly reduced Sirt3 level in many breast cancer cell lines, we aimed to clarify the effect of de novo Sirt3 expression upon hyperoxic treatment in the human MCF-7 breast cancer cells. De novo expression of Sirt3 decreased metabolic activity and cellular growth of MCF-7 cells, reduced expression of pro-angiogenic and epithelial mesenchymal transition genes, induced metabolic switch from glycolysis to oxidative phosphorylation, and decreased abundance of senescent cells. These effects were enhanced upon hyperoxic treatment: induction of DNA damage and upregulation of p53, with increase of ROS levels followed by mitochondrial and antioxidant dysfunction, resulted in additional reduction of metabolic activity and inhibition of cellular growth and survival. The mitigation of tumorigenic properties and enhancement of the susceptibility of the MCF-7 breast cancer cells to the hyperoxic treatment upon de novo Sirt3 expression, indicates that these factors, individually and in combination, should be further explored in vitro and particularly in vivo, as an adjuvant tumor therapy in breast cancer malignancies.

hyperoxia ; sirtuin 3 ; breast cancer ; mitochondria ; oxidative stress

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