title: JNK contributes to the tumorigenic potential of human cholangiocarcinoma cells through the mTOR pathway regulated GRP78 induction.
abstract: 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.
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Kai
authors.initials: K
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Song
authors.initials: S
authors.lastname: Su
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Duan
authors.affiliation: Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Shaokun
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Public Health, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Run
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Youping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Affiliated Hospital of Chinese Traditional Medicine, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Rongyang
authors.initials: R
authors.lastname: Dai
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; D048031:JNK Mitogen-Activated Protein Kinases