Nuclear EGFR impairs ASPP2-p53 complex-induced apoptosis by inducing SOS1 expression in hepatocellular carcinoma.
Nuclear EGFR impairs ASPP2-p53 complex-induced apoptosis by inducing SOS1 expression in hepatocellular carcinoma.
复制标题
核 EGFR 通过诱导肝细胞癌中 SOS1 的表达来损害 ASPP2-p53 复合物诱导的细胞凋亡
DOI：
10.18632/oncotarget.3757
复制
发表时间：
2015-06-30
期刊：
影响因子：
--
通讯作者：
Chen D
中科院分区：
文献类型：
--
作者：
Liu K;Jiang T;Ouyang Y;Shi Y;Zang Y;Li N;Lu S;Chen D
ASPP 2可以与p53结合，并通过将其引导至促凋亡基因的启动子来增强p53的凋亡能力。在此，ASPP 2过表达24小时通过增强促凋亡基因启动子上p53的反式激活瞬时诱导肝癌细胞凋亡。然而，长期ASPP 2过表达（超过48小时）未能诱导细胞凋亡，因为p53从促凋亡基因启动子释放。在非凋亡细胞中，细胞核EGFR通过直接结合到SOS 1启动子来诱导SOS 1表达。SOS 1激活HRAS/PI 3 K/AKT通路，导致p-AKT和Bcl-2核转位。p-AKT和ASPP 2之间的相互作用促进Bcl-2与p53的结合，从而从促凋亡基因启动子释放p53。体内试验表明，EGFR/SOS 1促进核p-AKT+、Bcl-2+细胞的生长导致肝癌细胞对ASPP 2-p53复合物诱导的凋亡的抗性，并且阻断EGFR的核转位显著改善和增强ASPP 2的促凋亡功能。最后，EGFR诱导的SOS 1对HRAS/PI 3 K/AKT通路的激活也抑制了顺铂诱导的细胞凋亡，这表明肝癌细胞中存在常见的凋亡逃避机制。由于逃避细胞凋亡有助于肝癌的治疗抗性，我们的研究结果也支持进一步研究EGFR和SOS 1的联合治疗阻断。
ASPP2 can bind to p53 and enhance the apoptotic capabilities of p53 by guiding it to the promoters of pro-apoptotic genes. Here, ASPP2 overexpression for 24 hours transiently induced apoptosis in hepatoma cells by enhancing the transactivation of p53 on pro-apoptotic gene promoters. However, long-term ASPP2 overexpression (more than 48 hours) failed to induce apoptosis because p53 was released from the pro-apoptotic gene promoters. In non-apoptotic cells, nuclear EGFR induced SOS1 expression by directly binding to the SOS1 promoter. SOS1 activated the HRAS/PI3K/AKT pathway and resulted in nuclear translocation of p-AKT and Bcl-2. The interaction between p-AKT and ASPP2 facilitates Bcl-2 binding to p53, which releases p53 from the pro-apoptotic gene promoters. The in vivo assay demonstrated that EGFR/SOS1-promoted growth of nuclear p-AKT+, Bcl-2+ cells results in the resistance of hepatoma cells to ASPP2-p53 complex-induced apoptosis and that blocking nuclear translocation of EGFR dramatically improves and enhances the pro-apoptotic function of ASPP2. Finally, the activation of the HRAS/PI3K/AKT pathway by EGFR-induced SOS1 also inhibits cisplatin-induced apoptosis, suggesting a common apoptosis-evasion mechanism in hepatoma cells. Because evasion of apoptosis contributes to treatment resistance in hepatoma, our results also support further investigation of combined therapeutic blockade of EGFR and SOS1.