Kim Sun-Yong, Kim Hyo Jeong, Byeon Hyung Kwon, Kim Dae Ho, Kim Chul-Ho
Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea.
Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
Oncotarget. 2017 Nov 30;8(66):110474-110489. doi: 10.18632/oncotarget.22793. eCollection 2017 Dec 15.
AKT (also known as protein kinase B, PKB) plays an important role in cell survival or tumor progression. For these reasons, AKT is an emerging target for cancer therapeutics. Previously our studies showed that mitochondrial E3 ubiquitin protein ligase 1 (MUL1, also known as MULAN/GIDE/MAPL) is suppressed in head and neck cancer (HNC) and acts as negative regulator against AKT. However, the MUL1 regulatory mechanisms remain largely unknown. Here we report that cisplatin (CDDP) induces thyroid cancer cell death through MUL1-AKT axis. Specifically, CDDP-induced MUL1 leads to ubiquitylation of active form of AKT. We also observed that the role of forkhead box O3 (FOXO3) is pivotal in CDDP-induced MUL1 regulation. FOXO3 knock-downed cells show resistance against CDDP-mediated MUL1-AKT axis. CDDP-mediated intracellular ROS increment plays an important role in FOXO3-MUL1-AKT signal pathway. The data provide compelling evidence to support the idea that the regulation of FOXO3-MUL1-AKT axis can be a novel strategy for the treatment of HNC with CDDP.
AKT（也称为蛋白激酶B，PKB）在细胞存活或肿瘤进展中起重要作用。基于这些原因，AKT成为癌症治疗中一个新兴的靶点。此前我们的研究表明，线粒体E3泛素蛋白连接酶1（MUL1，也称为MULAN/GIDE/MAPL）在头颈癌（HNC）中受到抑制，并作为AKT的负调节因子发挥作用。然而，MUL1的调节机制在很大程度上仍然未知。在此我们报告，顺铂（CDDP）通过MUL1-AKT轴诱导甲状腺癌细胞死亡。具体而言，CDDP诱导的MUL1导致活性形式的AKT发生泛素化。我们还观察到，叉头框O3（FOXO3）在CDDP诱导的MUL1调节中起关键作用。FOXO3敲低的细胞对CDDP介导的MUL1-AKT轴具有抗性。CDDP介导的细胞内活性氧增加在FOXO3-MUL1-AKT信号通路中起重要作用。这些数据提供了令人信服的证据，支持FOXO3-MUL1-AKT轴的调节可以成为用CDDP治疗HNC的一种新策略这一观点。
