title: A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission.
abstract: 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.
authors.affiliation: a College of Pharmacy; 3rd Military Medical University ; Chongqing , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Guobing
authors.initials: G
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Hu
authors.forename: Qian-Liang
authors.initials: QL
authors.lastname: Ming
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001343:Autophagy; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007546:Isoquinolines / Q000737:chemistry*; D008247:Lysosomes / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy; D009368:Neoplasm Transplantation; D010636:Phenols / Q000737:chemistry*; D034622:RNA Interference; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D010636:Phenols; D000090802:rab7 GTP-Binding Proteins; C080095:liensinine; D020558:GTP Phosphohydrolases; D020691:rab GTP-Binding Proteins; C110768:DNM1L protein, human; D034281:Dynamins
keywords: DNM1L; RAB7A; apoptosis; autophagic stress; autophagy; breast cancer; liensinine; lysosome; mitochondrial fission