基于肿瘤细胞的异常脂代谢探讨植物环肽RA-V抗乳腺癌转移作用及分子机制

Lipid metabolism reprogramming is an important biochemical base for the maintenance of malignant phenotypes of cancer cells, which is relative to tumor migration and invasion and becomes a hot topic in the field of anti-tumor drug discovery. However, few lead compounds have been reported to inhibit tumor lipid metabolism now. In our previous works, we found that plant cyclopeptide RA-V inhibited breast cancer in vitro and in vivo and has been pipelined as one potential anti-tumor lead compound in the team. In addition, RA-V inhibited migration, invasion and adhension of breast cancer cells, and showed a good regulation effect on lipid metabolism. Moreover, its inhibition effect on breast cancer cell invasion was mediated by the SREBP signal pathway, which was associated with lipid metabolism. But the mechanism is not clear. In this project, we will use biological and pathological technologies, such as plasmid transfection and frozen section, to investigate whether RA-V can inhibit breast cancer metastasis by regulating lipid metabolism reprogramming via the SREBP signal pathway. These findings aim to clarify the new mechanisms towards the anti-tumor activities of RA-V and provide some theoretical basis and experimental data for the new anti-tumor drug R&D.

脂代谢异常是维持肿瘤细胞恶性表型的重要生化基础，与其细胞迁移、侵袭等密切相关，是目前抗肿瘤药物研究热点。但是对靶向于脂代谢的抗肿瘤先导化合物报道较为有限，且作用机制尚不明晰。前期我们发现植物环肽RA-V具有良好的体内外抗乳腺癌活性，是极具潜力的抗肿瘤先导化合物，能抑制乳腺癌细胞迁移、侵袭和黏附；并首次发现RA-V对肿瘤脂代谢有良好的调控作用，可通过与脂代谢密切相关的SREBP通路发挥抗乳腺癌侵袭作用，但具体机制仍需进一步研究。据此，本研究试图在分子、细胞和动物水平，利用基因干扰、过表达等分子生物学手段，结合病理学技术方法，以SREBP通路为主线，乳腺癌为对象，系统考察RA-V通过SREBP通路抑制脂质合成，从而发挥抗肿瘤转移的效果，并探讨其具体作用机制。这些研究将为阐明RA-V抗肿瘤的新作用机制及其进入新药品种研发提供理论基础和实验数据。

脂代谢异常是维持肿瘤细胞恶性表型的重要生化基础，与其细胞迁移、侵袭等密切相关，是目前抗肿瘤药物研究热点。但是对靶向于脂代谢的抗肿瘤先导化合物报道较为有限，且作用机制尚不明晰。前期我们发现植物环肽RAs系列化合物具有良好的体内外抗肿瘤活性，是极具潜力的抗肿瘤先导化合物，能抑制乳腺癌细胞迁移、侵袭和黏附；并首次发现其对肿瘤脂代谢有良好的调控作用，可通过与脂代谢密切相关的SREBP通路发挥抗乳腺癌侵袭作用，但具体机制仍需进一步研究。在本项目的研究中，我们选取了抗肿瘤效果最好的植物环肽RA-XII。首先，在细胞水平明确了其抑制脂肪酸合成从而抑制肿瘤细胞增殖和诱导细胞周期阻滞的作用，其次在细胞水平明确其通过抑制SCAP-SREBP信号通路从而抑制肿瘤脂代谢的作用机制，最后，在动物体内验证其抗肿瘤的作用以及相应机制。通过此项研究将为阐明RA-XII抗肿瘤的新作用机制及其进入新药品种研发提供理论基础和实验数据。