title: SVCT-2 determines the sensitivity to ascorbate-induced cell death in cholangiocarcinoma cell lines and patient derived xenografts.
abstract: Cholangiocarcinoma (CC) is a devastating malignancy with late diagnosis and poor response to conventional chemotherapy. Recent studies have revealed anti-cancer effect of vitamin C (l-ascorbic acid, ascorbate) in several types of cancer. However, the effect of l-ascorbic acid (AA) in CC remains elusive. Herein, we demonstrated that AA induced cytotoxicity in CC cells by generating intracellular reactive oxygen species (ROS), and subsequently DNA damage, ATP depletion, mTOR pathway inhibition. Moreover, AA worked synergistically with chemotherapeutic agent cisplatin to impair CC cells growth both in vitro and in vivo. Intriguingly, sodium-dependent vitamin C transporter 2 (SVCT-2) expression was inversely correlated with IC50 values of AA. Knockdown of SVCT-2 dramatically alleviated DNA damage, ATP depletion, and inhibition of mTOR pathway induced by AA. Furthermore, SVCT-2 knockdown endowed CC cells with the resistance to AA treatment. Finally, the inhibitory effects of AA were further confirmed in patient-derived CC xenograft models. Thus, our results unravel therapeutic potential of AA alone or in combination with cisplatin for CC. SVCT2 expression level may serve as a positive outcome predictor for AA treatment in CC.
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Lv
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; Graduate School of Fujian Medical University, Fuzhou, Fujian Province 350108, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Fang
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai, China.
authors.forename: Guishuai
authors.initials: G
authors.lastname: Lv
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Han
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Dong
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai, China.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Beige
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China. Electronic address: gs_yang00@yahoo.com.
authors.forename: Guangshun
authors.initials: G
authors.lastname: Yang
authors.affiliation: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China. Electronic address: hywangk@vip.sina.com.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008819:Mice, Nude; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C555163:SLC23A2 protein, human; D060347:Sodium-Coupled Vitamin C Transporters; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D001205:Ascorbic Acid; D002945:Cisplatin
keywords: Ascorbic acid; Cholangiocarcinoma; ROS; SVCT-2