Auranofin sensitizes breast cancer cells to paclitaxel mediated cell death via regulating FOXO3/Nrf2/Keap1 signaling pathway.

Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a transcriptional factor which acts as a regulator for cellular oxidative stress, and tightly regulated by Kelch‐like ECH‐associated protein 1 (Keap1). In this study, we found that auranofin and paclitaxel combination treatment increased TUNEL positive apoptotic cells and enhanced the DNA damage marker γ‐H2AX in MCF‐7 and MDA‐MB‐231 breast cancer cells. The immunoblotting analysis revealed the combination of auranofin and paclitaxel significantly increased the FOXO3 expression in a concentration dependent manner. Further we observed that auranofin and paclitaxel treatment prevents the translocation of Nrf2 in a concentration dependent manner. The increased FOXO3 expression might be involved in the cytoplasmic degradation of Nrf1‐Keap1 complex. Further, the molecular docking results confirm auranofin act as the agonist for Foxo3. Therefore, the present results suggest that auranofin sensitize the breast cancer cells to paclitaxel via regulating FOXO3/Nrf2/Keap1signaling pathway. Significance Statement: The present results show that auranofin enhances paclitaxel induced TUNEL positive apoptotic cells. Further, auranofin treatment increases FOXO3 which in turn inhibit the dissociation of Nrf2 and Keap1 in both MDA‐MB‐231 and MCF‐7 cell lines. Therefore, the present results clearly illustrate the chemosensitizing property of auranofin via regulating FOXO3/Nrf2/Keap1 signaling pathway in the breast cancer cells. Auranofin is already a Food and Drug administration approved drug and it could be considered for the clinical applications after preclinical experimentation. [ABSTRACT FROM AUTHOR]