Feng Chunhong, He Kai, Zhang Chunyan, Su Song, Li Bo, Li Yuxiao, Duan Chun-Yan, Chen Shaokun, Chen Run, Liu Youping, Li Hong, Wei Mei, Xia Xianming, Dai Rongyang
Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China.
Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China.
PLoS One. 2014 Feb 28;9(2):e90388. doi: 10.1371/journal.pone.0090388. eCollection 2014.
Less is known about the roles of c-Jun N-terminal kinase (JNK) in cholangiocarcinoma (CCA). Here, we report that JNK exerts its oncogenic action in human CCA cells, partially due to the mammalian target of rapamycin (mTOR) pathway regulated glucose-regulated protein 78 (GRP78) induction. In human CCA cells, the phosphorylation of eukaryotic initiation factor alpha (eIF2α) results in the accumulation of activating transcription factor 4 (ATF4) and GRP78 independent of unfolded protein response (UPR). Suppression of GRP78 expression decreases the proliferation and invasion of human CCA cells. It's notable that mTOR is required for eIF2α phosphorylation-induced ATF4 and GRP78 expression. Importantly, JNK promotes eIF2α/ATF4-mediated GRP78 induction through regulating the activity of mTOR. Thus, our study implicates JNK/mTOR signaling plays an important role in cholangiocarcinogenesis, partially through promoting the eIF2α/ATF4/GRP78 pathway.
关于c-Jun氨基末端激酶（JNK）在胆管癌（CCA）中的作用，人们了解较少。在此，我们报告JNK在人CCA细胞中发挥致癌作用，部分原因是雷帕霉素靶蛋白（mTOR）途径调节的葡萄糖调节蛋白78（GRP78）的诱导。在人CCA细胞中，真核起始因子α（eIF2α）的磷酸化导致激活转录因子4（ATF4）和GRP78的积累，且不依赖于未折叠蛋白反应（UPR）。GRP78表达的抑制会降低人CCA细胞的增殖和侵袭。值得注意的是，mTOR是eIF2α磷酸化诱导的ATF4和GRP78表达所必需的。重要的是，JNK通过调节mTOR的活性促进eIF2α/ATF4介导的GRP78诱导。因此，我们的研究表明JNK/mTOR信号通路在胆管癌发生中起重要作用，部分是通过促进eIF2α/ATF4/GRP78途径。
