TopBP1激活P38 MAPK通路调控E2F1影响自噬在前列腺癌产生去势抵抗的机制研究

自噬是肿瘤产生耐药的重要途径，它能促进前列腺癌产生去势抵抗（CRPC），但具体调控机制不明。我们研究发现TopBP1可以促进自噬发生，并在CRPC产生过程中起到重要作用；在前列腺癌细胞中，TopBP1能够激活P38 MAPK通路，而该通路又是促进自噬的重要通路；P38 MAPK又可通过转录因子E2F1调控自噬基因表达。然而，前列腺癌在不同环境下，E2F1对自噬的调控方向不同；同时，文献报道TopBP1可抑制E2F1的功能，但我们研究显示高表达TopBP1及E2F1均提示前列腺癌高恶性度，临床与基础实验结果矛盾，E2F1在前列腺癌进展的作用不明确。因此，我们提出科学假说：在CRPC形成时，TopBP1激活P38 MAPK通路，通过调控E2F1来影响细胞自噬，使其适应去势。本项目通过调节TopBP1、P38 MAPK及E2F1的表达来研究自噬与CRPC的产生机制，为CRPC的治疗探索新靶点。

Autophagy is an important approach to drug-resistance. It is demonstrated to promote the development of castration-resistance prostate cancer (CRPC). However, the exact mechanism remains unclear. Our previous studies revealed that TopBP1 could promote the level of autophagy and played an important role in the development of CRPC. In prostate cancer cells, TopBP1 could activate the P38 MAPK pathway, which is an essential pathway to activate autophagy. P38 could also regulate autophagy genes expression through transcription factor E2F1. Nevertheless, when prostate cancer was in different conditions, the regulation of E2F1 on autophagy genes was in different directions. TopBP1 can inhibit the function of E2F1, while our previous studies showed that both higher expression of TopBP1 and E2F1 indicated higher malignancy of prostate cancer. There was contradiction between results of clinical and experimental data. Therefore, we propose a scientific hypothesis that TopBP1 can activate or inhibit E2F1 by activating the P38 pathway, which may result in the activation of autophagy and the development of CRPC. The study will explore a new therapeutic target for CRPC by investigating the relationship of autophagy and CRPC through regulating the expression of TopBP1, P38 MAPK and E2F1.