氯胍通过网格蛋白非依赖内吞促进EGFR泛素化降解抑制肌层浸润性膀胱癌生长的机制研究

肌层浸润性膀胱癌（MIBC）具有高侵袭、易转移和高死亡率的特点，迫切需要新的治疗手段。我们前期研究显示，氯胍显著抑制MIBC生长，远优于二甲双胍，但其作用机制不清楚。进一步研究发现，氯胍直接结合EGFR，促进EGFR泛素化，其泛素化过程不受网格蛋白调控。基于此，我们提出如下科学假说：氯胍与EGFR结合后，促进EGFR与Caveolin-1相互作用，招募泛素化酶Cbl，加速EGFR泛素化降解，从而遏制MIBC肿瘤细胞生长。因此，本项目拟开展以下重要研究：1）明确氯胍体内外抑制MIBC细胞活性的功能，探讨氯胍与吉非替尼的协同作用；2）揭示氯胍通过促进EGFR与Caveolin-1相互作用诱导EGFR泛素化的分子机制；3）利用PDX模型探讨EGFR水平对预测氯胍治疗MIBC个性化效果的临床意义。本项目将揭示氯胍抑制膀胱癌的功能及其分子机制，为治疗MIBC提供新的靶点和科学依据。

Muscle invasive bladder cancer (MIBC) is characterized with high invasion, vulnerability to metastasis and high mortality. Novel treatment strategy is urgently needed. Our previous results show that proguanil has much better anticancer activity than metformin. However, the mechanism underlying is unknown. Further study demonstrates that proguanil directly binds to EGFR and accelerates EGFR’s ubiquitination in non-clathrin endocytosis fashion. Based on these results, we hypothesize that after binding with EGFR, proguanil promotes the interaction between EGFR and Caveolin-1, recruits ubiquitination enzyme Cbl, enhances degradation of EGFR, then inhibits the growth of MIBC. Firstly, we will determine the functions that proguanil inhibits growth of MIBC both in vitro and in vivo, and explore the synergistic effect of proguanil and gefitinib. Secondly, we will reveal the molecular mechanisms that proguanil induces the ubiquitinization of EGFR by promoting the interaction between EGFR and Caveolin-1. Finally, we will explore clinic significance of the prediction potential of EGFR levels to therapeutic effect on MIBC by PDX model. This project will uncover the functions and molecular mechanisms that proguanil inhibits bladder cancer, and provide a novel target and scientific foundation for treating MIBC.