A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission
A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission
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一种新型自噬/线粒体自噬抑制剂莲心碱通过 DNM1L 介导的线粒体裂变使乳腺癌细胞对化疗敏感
DOI：
10.1080/15548627.2015.1056970
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发表时间：
2015-08-01
期刊：
影响因子：
13.3
通讯作者：
Gao, Ning
中科院分区：
文献类型：
--
作者：
Zhou, Jing;Li, Guobing;Gao, Ning
自噬抑制已被广泛接受为一种有前途的癌症治疗策略，但缺乏有效和特异性的自噬抑制剂阻碍了其应用。在这里，我们发现莲心碱，一种主要的异喹啉生物碱，通过阻断自噬体-溶酶体融合来抑制晚期自噬/线粒体自噬。这种作用可能是通过抑制RAB 7A向溶酶体而不是自噬体的募集来实现的。我们进一步研究了莲心碱抑制自噬对化疗药物疗效的影响，发现莲心碱的共同治疗显着降低了各种化疗药物治疗的乳腺癌细胞的生存力和增加凋亡。机制上，我们发现莲心碱抑制自噬/线粒体自噬通过触发线粒体分裂增强阿霉素介导的细胞凋亡，这是由DNM 1 L的去磷酸化和线粒体易位引起的。然而，通过药理学或遗传学方法阻断自噬体/线粒体吞噬体的形成显着减弱了联合治疗细胞中的线粒体分裂和凋亡。此外，莲心碱与阿霉素在体内协同抑制MDA-MB-231异种移植瘤的生长。我们的研究结果表明，莲心碱有可能进一步发展为一种新的自噬/线粒体自噬抑制剂，莲心碱与经典化疗药物的组合可能代表一种新的治疗乳腺癌的治疗策略。
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.