JNK Contributes to the Tumorigenic Potential of Human Cholangiocarcinoma Cells through the mTOR Pathway Regulated GRP78 Induction

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 N-端激酶（JNK）在胆管癌（CCA）中的作用知之甚少。本研究报告指出，JNK在人类CCA细胞中发挥其致癌作用，部分原因是由于哺乳动物雷帕霉素靶蛋白（mTOR）通路调控的葡萄糖调节蛋白78（GRP78）的诱导。在人类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，这一过程独立于未折叠蛋白反应（UPR）。抑制GRP78的表达可以降低人类CCA细胞的增殖和侵袭。值得注意的是，mTOR对于eIF2α磷酸化引发的ATF4和GRP78的表达是必需的。重要的是，JNK通过调节mTOR的活性，促进eIF2α/ATF4介导的GRP78的诱导。因此，本研究表明JNK/mTOR信号通路在胆管癌的发生发展中起着重要作用，部分是通过促进eIF2α/ATF4/GRP78通路实现的。