A Novel Autophagy/Mitophagy Inhibitor Liensinine Sensitizes Breast Cancer Cells To Chemotherapy Through DNM1L-mediated Mitochondrial Fission

Autophagy inhibition has been widely accepted as a promising therapeutic strategy in cancer, while lack of effective and specific autophagy inhibitors hinders its application. Here we found that liensinine, a major isoquinoline alkaloid, inhibits late stage autophagy/mitophagy through blocking autophagosome-lysosome fusion. This effect is likely achieved via inhibiting the recruitment of RAB7 A to lysosome but not to autophagosome. We further investigated the effects of autophagy inhibition by liensinine on the therapeutic efficacy of chemotherapeutic drugs and found that co-treatment of liensinine markedly decreased the viability and increased apoptosis in breast cancer cells treated with various chemotherapeutic agents. Mechanistically, we found that inhibition of autophagy/mitophagy by liensinine enhanced doxorubicin-mediated apoptosis by triggering mitochondrial fission, which is resulted from dephosphorylation and mitochondrial translocation of DNM1 L. However, blocking the autophagosome/mitophagosome formation by pharmacological or genetic approaches markedly attenuated mitochondrial fission and apoptosis in cells with combinational treatment. Moreover, liensinine was synergized with doxorubicin to inhibit tumor growth in MDA-MB-231 xenograft in vivo. Our findings suggest that liensinine could potentially be further developed as a novel autophagy/mitophagy inhibitor, and a combination of liensinine with classical chemotherapeutic drugs could represent a novel therapeutic strategy for treatment of breast cancer.?...