title: Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells.
abstract: Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.|Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Ding
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.|Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
authors.forename: Roongruedee
authors.initials: R
authors.lastname: Chaiteerakij
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Shaleh
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Boakye
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Ndzengue
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Shengbing
authors.initials: S
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zou
authors.affiliation: Hollings Cancer Center, Division of Hematology-Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Melanie B
authors.initials: MB
authors.lastname: Thomas
authors.affiliation: Apogee Biotechnology Corporation, Hummelstown, PA, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D009536:Niacinamide; D010671:Phenylurea Compounds; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077157:Sorafenib; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase
keywords: ABC294640; autophagy; cholangiocarcinoma; sorafenib; sphingosine kinase 2