DUSP12介导的内质网应激在诱导TRAIL耐药胰腺癌细胞凋亡的机制研究

如何突破胰腺癌耐药屏障是目前药物治疗领域的热点。我们前期发现，Triptolide通过下调DUSP12致敏TRAIL，诱导胰腺癌细胞凋亡，而机制不明。文献报道，DUSP12是双向特异性去磷酸化酶，在胰腺癌中高表达，其功能结合位点与PERK的磷酸化结构域有高度同源性。预实验证实，下调DUSP12水平抑制其去磷酸化作用，启动内质网应激的关键步骤：PERK-eIF2激活，而该信号通路可通过转录因子ATF-4对死亡受体信号分子调控，从而致敏TRAIL。据此，我们提出在TRAIL耐药胰腺癌中，DUSP12与PERK形成功能复合体。当Triptolide下调DUSP12后，解除其去磷酸化作用，诱导PERK自磷酸化，通过eIF2激活下游转录因子ATF-4，调控死亡受体相关信号分子，致敏TRAIL的假说。本研究有望阐明Triptolide突破胰腺癌细胞TRAIL耐受屏障的新机制，为胰腺癌的治疗提供新思路。

Pancreatic cancer is related with poor prognosis. Breakthrough drug resistance for pancreatic cancer is becoming a hot topic in medicine filed. Our previous research found that down-regulation of DUSP12 induces TRAIL resistance pancreatic cancer cells apoptosis. However, the detailed mechanism is still unclear. Further research indicated that DUSP12 is a dual specificity phosphatase, which is overexperssed in pancreatic cancer cells. The functional binding site of DUSP12 is similar to the phosphorylation site of PERK. We have proved that down-regulation of DUSP12 could inhibit its dephosphorylation, which initiates a key step of Endoplasmic Reticulum Stress: activation of PERK-eIF2. And the activaiton of PERK-eIF2 regulates death receptor signals through transcriptional factor: ATF-4, which further sensitizes TRAIL. Therefor, we provide the hypothesis as follows, DUSP12 bind with PERK and form a stable functional complex in TRAIL resistance pancreatic cancer cells. Down-regulaiton of DUSP12 by Triptolide activate death receptor signals through phosphorylation of ER stress key factor: PERK-eIF2. This project elaborates the mechanism of regulation of death receptor signals by Triptolide through oncogene DUSP12---PERK-eIF2 signal pathway. Since TRAIL is already in use against several cancers, understanding the mechanism by which Triptolide sensitizes pancreatic cancer cells to TRAIL may result in a novel therapeutic strategy against pancreatic cancer.