A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission

• Published in: Autophagy 2015-01, Vol.11 (8), p.1259-1279
• Main Authors: Zhou, Jing, Li, Guobing, Zheng, Yi, Shen, Han-Ming, Hu, Xiaoye, Ming, Qian-Liang, Huang, Cheng, Li, Peng, Gao, Ning
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Apoptosis; autophagic stress; Autophagy; Basic Research Paper; breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Survival; DNM1L; Female; Gene Expression Regulation, Neoplastic; GTP Phosphohydrolases - metabolism; Humans; Hydrogen-Ion Concentration; Isoquinolines - chemistry; liensinine; lysosome; Lysosomes - metabolism; MCF-7 Cells; Mice; Mice, Nude; Microscopy, Electron, Transmission; Microtubule-Associated Proteins - metabolism; Mitochondrial Degradation; Mitochondrial Dynamics - physiology; mitochondrial fission; Mitochondrial Proteins - metabolism; Neoplasm Transplantation; Phenols - chemistry; rab GTP-Binding Proteins - metabolism; RAB7A; RNA Interference
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2015.1056970

Autophagy inhibition has been widely accepted as a promising therapeutic strategy in cancer, while the 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 RAB7A to lysosomes but not to autophagosomes. We further investigated the effects of autophagy inhibition by liensinine on the therapeutic efficacy of chemotherapeutic drugs and found that cotreatment 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 resulted from dephosphorylation and mitochondrial translocation of DNM1L. However, blocking autophagosome/mitophagosome formation by pharmacological or genetic approaches markedly attenuated mitochondrial fission and apoptosis in cells with combinatatorial 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.