Effects of inhibitors of mitochondrial oxidative phosphorylation on paclitaxel resistance and cellular senescence in drug-resistant triple-negative breast cancer cells
NIU Li-gang,ZHOU Yu-hui,ZHOU Can
Department of Breast Surgery, The First Affiliated Hospital of Xi′an Jiaotong University, Xi'an, Shaanxi 710061,China
Abstract:
Objective To investigate the effect of mitochondrial oxidative phosphorylation inhibitors on senescence of paclitaxel-resistant triple-negative breast cancer cells. Methods The triple-negative breast cancer cells MDA-MB-231 resistant to doxorubicin hydrochloride (DOX) MDA-MB-231/DOX were constructed. Thereafter, different concentrations (0.05, 0.1 and 0.2 μmol/L OXPHOS inhibitor) and different treatment time (24 h, 48 h and 72 h) on the viability of MDA-MB-231/DOX cells were detected by CCK-8. Mitochondrial respiration capacity of the two groups was compared by mitochondrial pressure measurement, and cell cycle changes were compared by Flow Cytometry. The expression of p53, p21, p16, peroxisome proliferator-activated receptor γ-coactivation factor 1α (PGC-1α) and mitochondrial dynamic-associated protein-1 (Drp1) in the two groups were compared by western blot. Results Compared with MDA-MB-231/DOX cells, the maximum respiratory capacity, spare respiratory capacity and ATP synthesis capacity of MDA-MB-231/DOX+OXPHOS inhibitor cells were significantly decreased (P <0.01), and proton leakage was increased (P <0.001). Compared with MDA-MB-231/DOX cells, the cell cycle detection results showed that the proportion of G0/G1 phase cells in MDA-MB-231/DOX+OXPHOS inhibitor group was significantly increased, and the proportion of S phase cells and G2/M phase cells was significantly decreased (P <0.05). It was accompanied by up-regulation of p53, p21 and p16 proteins (P <0.001). Furthermore, compared with MDA-MB-231/DOX cells, PGC1-α and Drp1 expressions in MDA-MB-231/DOX+OXPHOS inhibitor groups were significantly decreased (P <0.001). Conclusion OXPHOS inhibitors can reduce paclitaxel resistance in MDA-MB-231/DOX cells and induce cell senescence, which may be related to the inhibition of PGC-1α/Drp1 signaling pathway.
