title: Hepatitis B virus enhances cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 Kda.
abstract: Cisplatin is a classical platinum-based chemotherapeutic drug used in the treatment of many cancer types, including hepatocellular carcinoma (HCC). The application of cisplatin is significantly limited by its toxicity, which may be affected by various biological factors. Persistence of Hepatitis B virus (HBV) infection leads to HCC development and may be associated with higher incidence of severe hepatitis during chemotherapy. However, whether HBV alters the susceptibility of hepatocytes to cisplatin remains poorly understood. Here, we demonstrate that HBV transfection enhanced cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 KDa (Grp78), a major stress-induced chaperone that localizes to the endoplasmic reticulum. Silencing Grp78 gene increased the susceptibility of HepG2 to cisplatin by activating caspase-3. Grp78 expression was down-regulated by HBV infection both in vitro and in liver tissues of patients. We compared the cisplatin sensitivity of hepatoma cells either expressing (HepG2.2.15 cells) or not expressing the entire Hepatitis B Virus genome (HepG2). HepG2.2.15 cells showed increased sensitivity to cisplatin and a higher apoptosis rate. Overexpression of Grp78 counteracted the increase of sensitivity of HepG2.215 cells to cisplatin. Furthermore, we found that HBV disrupted Grp78 synthesis in response to cisplatin stimulation, which may trigger severe and prolonged endoplasmic reticulum (ER) stress that can induce cellular apoptosis. Our findings provide new information into the effect of HBV in the modulation of Grp78 expression, and, consequently on cisplatin-induced hepatotoxicity during viral infection.
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China; Department of Laboratory Medicine, Affiliated Pu'ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, PR China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China.
authors.forename: HuiOu
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China.
authors.forename: Huifen
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Medical College of Wuhan University of Science and Technology, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, PR China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, PR China.
authors.forename: Yiwu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China. Electronic address: adaleip@hust.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Lei
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, PR China. Electronic address: shenguanxin@hust.edu.cn.
authors.forename: Guanxin
authors.initials: G
authors.lastname: Shen
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D002945:Cisplatin
keywords: Cisplatin; Glucose-regulated protein of 78 KDa; Hepatitis B virus; Hepatotoxicity