EVI1和GSTP1-1在肿瘤细胞中相互作用和靶向药物的研究

药物耐受是肿瘤治疗失败的主要原因，寻找新的耐药机制和开发新型靶向药物是治愈肿瘤的关键。EVI1是一种致癌转录因子，在多种血液肿瘤和实体瘤中表达，与治疗预后不良、复发和耐药密切相关。然而，EVI1作为潜在的耐药因子，其作用机制不清，无靶向药物。除已知的EVI1诱导抗凋亡蛋白Bcl-xL和Mcl-1表达外，我们首次发现EVI1与谷胱甘肽转移酶P1-1（GSTP1-1）表达正相关，与JNK蛋白形成三者复合体，阻断JNK活化和凋亡。我们改造的依他尼酸衍生物6s具有抑制GSTP1-1活性和降解EVI1蛋白的双重功能，诱导JNK活化和细胞凋亡，对EVI1表达的细胞在体内和体外都具有明显的抑制作用。本课题将研究EVI1，GSTP1-1和JNK相互作用和调控网络，解析6s抑制EVI1表达的肿瘤生长和降解EVI1机制，解析EVI1诱导药物耐受新机制，为靶向EVI1表达的肿瘤提供新的途径和药物。

Resistance to chemotherapy is a key problem of therapeutic failure of cancer. New drug resistant factors and targeting agents need to be developed. EVI1 is an oncogenic transcription factor amplified or induced in many types of resistant and relapsed cancers and predicts poor prognosis. However, EVI1 as a potential drug resistance factor， the mechanism of action is not clear. In addition to the known regulation of EVI1 on the expression of anti-apoptotic protein Bcl-xL and Mcl-1, we found that EVI1 expression correlated with the expression of glutatione s-transferase P1-1 (GSTP1-1), a drug metabolic enzyme, and that EVI1/GSTP1-1/JNK form a complex blocking JNK action and apoptosis induction. We find the novel ethacrynic acid derivative 6s degrades EVI1 protein, inhibits GSTP1-1 activity, and induces JNK activation and apoptosis in EVI1 expressing cells. We will dissect the interaction network of EVI1/GSTP1-1/JNK and the mechanism of 6s to interrupting this network as well as the mechanism of EVI1 degradation and apoptosis induction. We aim to explore a new pathway of EVI1 causing drug resistance and to provide a new strategy to target EVI1 expressing cancer cells.