Liu Jie, Wang Guang-Hui, Duan Ying-Hui, Dai Yi, Bao Yuzhou, Hu Mengjie, Zhou Yu-Qi, Li Mingyu, Jiang Fuquan, Zhou Hu, Yao Xin-Sheng, Zhang Xiao-Kun
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, China.
Institutes of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, China.
Oncotarget. 2017 Jul 13;8(41):69731-69745. doi: 10.18632/oncotarget.19227. eCollection 2017 Sep 19.
Orphan nuclear receptor Nur77 promotes apoptosis by targeting mitochondria through interaction with Bcl-2, an event that converts Bcl-2 from a survival to killer. However, how the Nur77-Bcl-2 apoptotic pathway is regulated remains largely unknown. In this study, we examined the regulation of the Nur77-Bcl-2 pathway by CCE9, a xanthone compound. Our results demonstrated that the apoptotic effect of CCE9 depended on its induction of Nur77 expression, cytoplasmic localization, and mitochondrial targeting. The activation of the Nur77-Bcl-2 pathway by CCE9 was associated with its activation of p38α MAPK. Inhibition of p38α MAPK activation by knocking down or knocking out p38α MAPK impaired the effect of CCE9 on inducing apoptosis and the expression and cytoplasmic localization of Nur77. In addition, CCE9 activation of p38α MAPK resulted in Bcl-2 phosphorylation and Bcl-2 interaction with Nur77, whereas inhibition of p38α MAPK activation or expression suppressed the interaction. Moreover, mutating Ser87 and Thr56 in the loop of Bcl-2, which are known to be phosphorylated by p38α MAPK, impaired the ability Bcl-2 to interact with Nur77. Together, our results reveal a profound role of p38α MAPK in regulating the Nur77-Bcl-2 apoptotic pathway through its modulation of Nur77 expression, Bcl-2 phosphorylation, and their interaction.
孤儿核受体Nur77通过与Bcl-2相互作用靶向线粒体来促进细胞凋亡，这一过程将Bcl-2从一种促生存蛋白转变为促凋亡蛋白。然而，Nur77-Bcl-2凋亡途径是如何被调控的，目前仍 largely未知。在本研究中，我们研究了氧杂蒽酮化合物CCE9对Nur77-Bcl-2途径的调控作用。我们的结果表明，CCE9的凋亡效应取决于其对Nur77表达、细胞质定位和线粒体靶向的诱导作用。CCE9对Nur77-Bcl-2途径的激活与其对p38α MAPK的激活有关。通过敲低或敲除p38α MAPK抑制p38α MAPK的激活，会削弱CCE9诱导细胞凋亡的作用以及Nur77的表达和细胞质定位。此外，CCE9对p38α MAPK的激活导致Bcl-2磷酸化以及Bcl-2与Nur77相互作用，而抑制p38α MAPK的激活或表达则会抑制这种相互作用。此外，在Bcl-2环中已知可被p38α MAPK磷酸化的Ser87和Thr56位点进行突变，会损害Bcl-2与Nur77相互作用的能力。总之，我们的结果揭示了p38α MAPK在通过调节Nur77表达、Bcl-2磷酸化及其相互作用来调控Nur77-Bcl-2凋亡途径中所起的重要作用。
