title: Targeting hexokinase II as a possible therapy for cholangiocarcinoma.
abstract: Overexpression of hexokinase 2 (HKII) has been demonstrated in various cancers. A number of in vitro and in vivo studies in several cancers show the significance of HKII in many cellular processes including proliferation, metastasis and apoptosis. However, the role of HKII in Opisthorchis viverrini (Ov) associated cholangiocarcinoma (CCA) is still unknown. In the present study, the expression and roles of HKII were determined in Ov associated CCA. The expression of HKII was investigated in 82 patients with histologically proven CCAs by immunohistochemistry. HKII was distinctively expressed in CCA tissues. It was rarely expressed in normal bile duct epithelium, but was expressed in hyperplastic/dysplastic and in 82% of CCA bile ducts. The observation was confirmed in the Ov associated hamster model. Suppression of HKII expression using siRNA significantly decreased cell proliferation, migration and invasion of CCA cell lines. Similar results were obtained using lonidamine (LND), an inhibitor of HK. LND significantly inhibited growth of 4 CCA cell lines tested in dose and time dependent fashion. Comparison the cytotoxic effects of LND and siRNA-HKII suggests the off target of LND above 100 μM. In addition, LND in non-cytotoxic doses could suppress migration and invasion of CCA cells. These results indicate the association of HKII in cholangiocarcinogenesis and progression and suggest the possibility of HKII as a therapeutic target for CCA.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Ubonrat
authors.initials: U
authors.lastname: Thamrongwaranggoon
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: wunchanas@yahoo.com.
authors.forename: Wunchana
authors.initials: W
authors.lastname: Seubwai
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Chatchai
authors.initials: C
authors.lastname: Phoomak
authors.affiliation: Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Sakkarn
authors.initials: S
authors.lastname: Sangkhamanon
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Ubon
authors.initials: U
authors.lastname: Cha'on
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Thidarat
authors.initials: T
authors.lastname: Boonmars
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Sopit
authors.initials: S
authors.lastname: Wongkham
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006224:Cricetinae; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D009891:Opisthorchis / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D006593:Hexokinase; C016371:lonidamine
keywords: Cholangiocarcinoma; Hexokinase 2; Lonidamine; Opisthorchis viverrini