莲心碱抑制自噬降解及调节线粒体分裂增敏乳腺癌化疗的分子机制

发布时间：2018-04-22 18:16

本文选题：莲心碱 + 乳腺癌　；参考：《第三军医大学》2015年硕士论文

【摘要】：抑制自噬(Autophagic inhibition)是一种被广泛接受的有效的癌症治疗策略,但是缺乏有效的和特异的靶向自噬的药物限制了这一策略的应用。在本课题中,我们发现了一种来源于莲子心的天然生物碱——莲心碱(Liensinine),可以通过抑制自噬小体(Autophagosome)与溶酶体(Lysosome)的融合,从而抑制自噬降解过程。莲心碱对自噬小体招募RAB7A过程没有显著影响,其抑制自噬小体与溶酶体的融合的分子机制可能是抑制溶酶体招募RAB7A蛋白过程。我们进一步研究了莲心碱的抑制自噬降解作用在肿瘤治疗中的应用,发现莲心碱与多种临床化疗药物联合作用于乳腺癌细胞系MDA-MB-231或MCF-7,可以显著增强这些化疗药物的诱导凋亡作用。通过机制研究,我们发现莲心碱协同多柔比星(Doxorubicin)能够去磷酸化DNM1L Ser637位点,从而增强DNM1L的线粒体转位,导致线粒体的过度分裂,加剧乳腺癌细胞凋亡。进一步研究,我们还发现过度的自噬小体聚集所导致的自噬性应激在莲心碱协同多柔比星诱导的一系列改变中发挥重要作用,通过药物手段或基因干扰手段减少自噬性应激可以有效阻断莲心碱协同多柔比星的协同效果。同时我们还利用体内实验对这一系列机制进行了论证。通过本研究的实验论证,我们认为莲心碱是一种新型的抑制自噬降解的药物,并且,莲心碱与常规化疗药物协同治疗乳腺癌可能成为一种新的化疗方案。
[Abstract]:Inhibition of autophagic inhibition is a widely accepted and effective cancer treatment strategy, but its application is limited by the lack of effective and specific targeted autophagy drugs. In this study, we found a natural alkaloid from lotus seed, Liensinineus, which can inhibit the degradation of autophagosome by inhibiting the fusion of Autophagosome and lysosome. Liensinine had no significant effect on the recruitment of RAB7A from autophagy. Its molecular mechanism of inhibiting the fusion of autophagy and lysosome might be the inhibition of lysosomal recruitment of RAB7A protein. We further studied the effect of liensinine on the inhibition of autophagy in the treatment of cancer. It was found that the combination of liensinine and various clinical chemotherapeutic drugs on breast cancer cell line MDA-MB-231 or MCF-7 could significantly enhance the apoptosis induced by these chemotherapeutic drugs. Through the study of mechanism, we found that liensinine combined with doxorubicin can dephosphorylate DNM1L Ser637 site, thus enhancing mitochondrial translocation of DNM1L, resulting in excessive division of mitochondria and exacerbating apoptosis of breast cancer cells. Further studies have also found that autophagy stress caused by excessive autophagy body aggregation plays an important role in a series of changes induced by liensinine in combination with doxorubicin. The synergistic effect of liensinine and doxorubicin could be effectively blocked by reducing autophagic stress by drug or gene interference. At the same time, we also use in vivo experiments to demonstrate this series of mechanisms. In this study, we conclude that liensinine is a new drug to inhibit autophagy degradation, and that the combination of liensinine and conventional chemotherapeutic drugs may become a new chemotherapy regimen for breast cancer.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R737.9

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