title: Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma.
abstract: Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chueh-Chuan
authors.initials: CC
authors.lastname: Yen
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chi-Tung
authors.initials: CT
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ren-Chin
authors.initials: RC
authors.lastname: Wu
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing-Hua University, Hsinchu, Taiwan.
authors.forename: Chung-Shan
authors.initials: CS
authors.lastname: Yu
authors.affiliation: Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Yi-Hsiu
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Peter Mu-Hsin
authors.initials: PM
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Han
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Institute of Clinical Medicine and Institute of Biopharmaceutical Sciences National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tzu Chi
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine and Institute of Biopharmaceutical Sciences National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000605:Amino Alcohols / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D001652:Bile Ducts / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000605:Amino Alcohols; D002518:Ceramides; C471998:JTE 013; D008246:Lysophospholipids; C544832:N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; C466999:SPHKAP protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine
keywords: SK1-I; cholangiocarcinoma; sphingosine kinase 1; sphingosine-1-phosphate; sphingosine-1-phosphate receptor 2