莲心碱影响乳腺癌细胞自噬的分子机制研究

Breast cancer is the most common female malignant tumor with the obviously rising incidence recently in China. Development of the novel therapeutic targets and drugs for treating breast cancer has attracted attention worldwidly. The extract from the Chinese herbal medicine called liensinine is proved to be effective component with high content, little side effects and easy extraction. Our previous studies suggest that liensinine inhibits autophagy of breast cancer cells with the accumulated autophagysomes and substrates. This project is based on the existing work and trying to figure out how PI3K-AKT-mTOR signal pathway responding to the liensinine treatment. In-depth study will illuminate the molecular mechanism of autophagy affected by liensinine according to cell experiments and animal study. This study is the first one to propose liensinine may block autophagy of breast cancer cells and will further clarify the molecular mechanism which will open new sight of liensinine, the effective components of traditional Chinese medicine pharmacology, for providing the novel therapeutic targets for breast cancer and supporting the potential application of liensinine in cancer chemotherapy and chemoprevention.

乳腺癌是女性最常见的恶性肿瘤，近年来我国乳腺癌发病率呈明显上升趋势，寻找治疗乳腺癌新靶点和药物一直是国际关注的热点。中草药有效成分莲心碱具有含量较高，提取简易，毒副作用较小的优点。我们的前期研究提示，莲心碱影响乳腺癌细胞的自噬，表现为自噬小体和底物的增加，推测其抑制了自噬的进行。本项目在已有的工作基础上，将进一步明确莲心碱对PI3K-AKT-mTOR信号途径的影响，结合细胞实验和动物模型深入研究莲心碱影响自噬的分子机制。本研究首次提出了莲心碱影响乳腺癌细胞的自噬，并深入探讨其分子机制，将有助于开启我国传统中药有效成分莲心碱药理学作用的新认识，为乳腺癌的治疗提供新的干预靶点，还为今后将莲心碱开发为高效、低毒的抗癌新药奠定药理学基础。

抑制自噬是近年来备受关注的一种癌症治疗策略，但其应用由于缺乏有效特异的靶向自噬的药物而受到限制。本项目研究发现来源于莲子心的天然生物碱—莲心碱，可以通过抑制溶酶体招募RAB7A蛋白，抑制自噬小体与溶酶体的融合，从而抑制自噬降解过程。进一步探讨莲心碱在肿瘤治疗中的应用，发现莲心碱可以协同多种临床化疗药物显著诱导乳腺癌细胞系MDA-MB-231和MCF-7的凋亡。通过机制研究，发现莲心碱能够协同多柔比星去磷酸化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；并且通过抑制剂或基因干扰手段证明过度的自噬小体聚集所致自噬性应激在莲心碱增敏乳腺癌化疗中起着重要作用。同时采用裸鼠异种移植瘤模型对这一系列机制进行了体内验证。通过本项目的研究，我们认为莲心碱是一种新型的抑制自噬降解的药物，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。