Upregulated mitophagy promotes the survival and aggressiveness of breast cancer upon apoptosis reversal

Abstract A number of literature have documented the phenomenon of apoptosis reversal. We have previously reported that when cancer cells are treated with apoptosis inducer, if the inducer is withdrawn at an inappropriate time, some cells would undergo apoptosis reversal and survive with increased aggressiveness. However, the reasons underlying the increase in aggressiveness are unknown. Here, we aimed to investigate whether enhanced mitophagy is the underlying rescuing force. By qPCR and flow cytometry, mitophagy-related genes and mitophagy activity were found to be upregulated upon apoptosis reversal of breast cancer cells. Decreasing mitophagy by molecular or pharmacological tools inhibited the survival and proliferation of apoptosis reversed cells. Importantly, knockdown of PINK1/BNIP3 decreased the tumorigenicity of apoptosis reversed breast cancer cells in vivo as revealed by nude mouse xenograft assay. Further, while therapeutic drug tamoxifen decreased the tumoigenicity, co-treatment of mitophagy inhibitor with tamoxifen further suppressed the tumor growth. Mechanistically, knockdown of PINK1/BNIP3 potentiated STS-induced apoptosis. Our results suggest that mitophagy promotes the survival and aggressiveness of breast cancer upon apoptosis reversal. Inhibiting mitophagy effectively decreases apoptosis reversal and enhances apoptotic inducers’ effect. Our study reveals a novel strategy of targeting mitophagy as a way to avoid cancer relapse after cancer drug treatment.