title: Simvastatin exerts anti-hepatitis B virus activity by inhibiting expression of minichromosome maintenance protein 7 in HepG2.2.15 cells.
abstract: Simvastatin (SIM), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to inhibit the activity of hepatitis B virus (HBV), however, the mechanism underlying its antiviral function remains unknown. Minichromosome maintenance (MCM) 7, a component of the MCM complex, has been reported to act as an important host factor aiding virus genome replication in host cells. The present study demonstrated that downregulation of MCM7 inhibited the expression of proteins transferred by adenoviral vectors. This suggests an association between MCM7 and viral DNA expression. Thus, the current study aimed to investigate whether SIM affected MCM7 expression. Notably, the results of the present study indicated that following exposure to SIM the protein expression levels of MCM7 in HepG2.2.15, a human HBV‑transfected liver cell line, was decreased. In addition, the HBV DNA replication in the cell line was suppressed. As quantitative polymerase chain reaction experiments demonstrated that SIM did not downregulate the mRNA expression level of MCM7, the current study further investigated whether SIM affects the translation of MCM7. Western blot experiments indicated that SIM improved the activation of eukaryotic initiation factor‑2α (eIF2α), a protein synthesis initiation factor, and upregulated the upstream factors of eIF2α, protein kinase RNA‑like endoplasmic reticulum kinase, which is regulated by the liver kinase B1 (LKB1)‑AMP‑activated protein kinase (AMPK) signaling pathway. These results indicated that SIM induced HBV downregulation via an MCM‑dependent mechanism, and SIM may inhibit MCM7 expression by increasing the phosphorylation of eIF2α, which is mediated by the LKB1-AMPK signaling pathway.
authors: Translational Medical Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Wenjie
authors: W
authors: Li
authors: Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors: Fei
authors: F
authors: Cao
authors: Translational Medical Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Juan
authors: J
authors: Li
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Zhixin
authors: Z
authors: Wang
authors: Department of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Yu
authors: Y
authors: Ren
authors: Translational Medical Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Zheyong
authors: Z
authors: Liang
authors: Translational Medical Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Peijun
authors: P
authors: Liu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D064168:Minichromosome Maintenance Complex Component 7 / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D034741:RNA, Small Interfering; D019821:Simvastatin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7