苗药蜘蛛香反向调节野生型和突变型p53介导乳腺癌细胞自噬和凋亡的作用及机制研究

项目组根据中医乳腺癌理论选取具有行气止痛、化痰祛瘀、散结消肿功效的苗药蜘蛛香进行体内外抗乳腺癌活性追踪，首次成功发现低毒高效的蜘蛛香抗乳腺癌有效部位F3。初步机理研究发现F3可同时上调野生型p53和下调突变型p53的表达，诱导乳腺癌细胞的凋亡和自噬。基于这一新发现，本项目提出“蜘蛛香反向同时调节野生型和突变型p53介导乳腺癌细胞自噬和凋亡的作用机制”假说，并结合药理学、分子生物学等最新研究进展，运用活体生物发光成像、基因敲除等技术，在深入研究F3抗乳腺癌作用的基础上，重点从基因表达调控和蛋白质稳态调控两方面阐明F3对野生型和突变型p53反向调节的分子机制，探讨该反向调节作用在诱导细胞凋亡和自噬中的角色，从而在细胞和分子水平阐明F3抗乳腺癌的作用机制。为开发基于同时调节突变型和野生型p53的抗乳腺癌分子靶向药物提供理论依据，也为民族药物现代化提供新思路和新方法，具有重要的理论意义和应用价值。

According to the theories of traditional Chinese medicine (TCM), the project team selected the Miao medicine Valeriana jatamansi Jones which has these effects of “promoting qi circulation to stop pain” and “reducing phlegm to remove blood stasis” and “eliminating stagnation to relieve swell”, and for the first time, found an active fraction F3 with low toxicity and high efficacy by the tracking of anti-breast cancer activity in vivo and in vitro. Preliminary mechanistic study revealed that F3 can not only up-regulate the expression of wild-type p53 but also down-regulate the expression of mutant p53 at the protein level, and also, F3 can induce apoptosis and autophagy in breast cancer cells. Based on this new discovery, this project propose a hypothesis “Valeriana jatamansi Jones induces autophagy and apoptosis through reverse regulation of wild-type and mutant p53 in breast cancer cells”. With reviewing the recent advances in pharmacology and molecular biology and applying the advanced technology including in vivo bioluminescence imaging and gene knockout, the project team will continue to intensively study the effects of F3 on breast cancer. On the basis of this, the project team will elucidate the molecular mechanisms of F3 in reverse regulation of wild-type and mutant p53 from two aspects of gene expression regulation and protein homeostasis, and investigate the roles of reverse regulation in inducing apoptosis and autophagy, then elucidate the mechanisms of F3 against breast cancer at the cellular and molecular level. This study can not only provide a theoretical base for the development of molecular-targeted drugs for breast cancer based on simultaneous regulation of both mutant and wild-type p53, but also provide new ideas and theories for the modernization of national medicine. It is significant to the theoretical research and practical applications.