TNF-α induces mitochondrial dysfunction to drive NLRP3/Caspase-1/GSDMD-mediated pyroptosis in MCF-7 cells

Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine, and some studies have shown that TNF-alpha can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-alpha exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-alpha on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-alpha and found that TNF-alpha induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-alpha on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-alpha-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-alpha on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-alpha on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-alpha-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-alpha exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer.