engleski

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

Sirtuin 3 (Sirt3) is the only member of sirtuin family linked to longevity in humans. In addition, important cellular and mitochondrial processes, including reactive oxygen species (ROS) generation are integrated through Sirt3. Furthermore, 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. Breast cancer is the most frequent cancer among women, and ranks as the fifth cause of cancer death worldwide. Since breast cancer cells have strikingly reduced Sirt3 level, and even 20% of them have almost no detectable Sirt3 protein we wanted to examine the effect of de novo Sirt3 expression upon treatment with 95% O 2 (hyperoxia) in human MCF-7 breast cancer cells model. Since hypoxia is a hallmark of various tumors, we hypothesized that hyperoxia would have negative impact on cancer cells, thus providing therapeutic strategy against their tumorigenic properties. Therefore, in this study we have developed human MCF-7 breast cancer cells transfectants expressing the Sirt3 protein in order to test its potential in affecting the response of these cells upon the hyperoxic treatment, i.e. to decipher whether it sensitizes or makes these cancer cells more resistant to oxidative stress. 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 the impact of these factors, individually and in combination, should be further explored in vitro and particularly in vivo in breast cancer malignancies.

Hyperoxia ; MCF-7 ; ROS ; mitochondrial function ; sirtuin 3

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