白花地胆草单体EM12靶向MDM2/p53负反馈环抗肿瘤作用及其分子机制

MDM2/p53通路是肿瘤治疗的重要靶点，尚无有效靶向药物。MDM2在肿瘤组织高表达，而在癌旁组织及正常组织低表达或不表达。我们研究发现白花地胆草单体EM12对多种肿瘤细胞具有杀伤作用，且其杀伤效应与肿瘤细胞的p53状态有关，以p53野生型显著，而对p53突变或缺失型杀伤效果不佳。我们进一步发现EM12靶向MDM2蛋白，诱导MDM2与p53解离，减少p53泛素化降解，进而发挥抗肿瘤作用。然而，EM12抗肿瘤作用分子机制仍不清晰，本课题我们在前期实验基础上，将深层次解析EM12抑制MDM2/p53负反馈环，重点阐释EM12解除MDM2对p53的抑制，增加肿瘤细胞p53稳定，发挥内源性抗肿瘤作用的分子机制；并进一步研究EM12联合DNA损伤药物的协同增效作用，为EM12应用于临床治疗野生型p53肿瘤提供实验依据，也为其它靶向MDM2/p53负反馈环的药物临床应用提供指导。

The MDM2/p53 pathway is a key target in tumor therapy. However, there was no drug targeting the MDM2/p53 pathway available on the market right now. Studies have shown that the expression of MDM2 was high in tumor tissues, but low or absent in para-cancer and normal tissues. In our preliminary experiments, we found that monomer EM12, purified from Elephantopus mollis H.B.K, had a significant anti –tumor effect, which was related to the p53 expression state in tumor cells. It was highly effective in tumors expressing wild-type p53, but not in tumors expressing mutant- or deletion-type p53. More interestingly, we found that EM12 inhibited tumor growth by binding to the MDM2 protein, which further promoted the dissociation of MDM2 and p53, and reduced the ubiquitination degradation of p53. However, the precise mechanism is not clearly understood. Therefore, in this study we will further elucidate the mechanism involved in the EM12-induced inhibition of the negative feedback loop of MDM2/p53, release of the inhibition of MDM2 on p53 and increase of p53 protein stability in tumor cells. In addition, we will also explore the synergistic effect of EM12 combined with DNA damage drugs, which will provide the experimental basis for the future clinical application of EM12 in the treatment of the wild-type p53 tumors and also the clinical guidance for other drugs targeting the negative feedback loop of MDM2/p53 pathway.