The role of helioxanthin in inhibiting human hepatitis B viral replication and gene expression by interfering with the host transcriptional machinery of viral promoters.
A non-nucleosidic compound, Helioxanthin (HE-145), was found to suppress HBV gene expression and replication in HCC cells. To understand the molecular mode of action of HE-145 on HBV gene expression, the effects of HE-145 on four viral promoter activities using luciferase as a reporter were examined. It was found that HE-145 selectively suppresses surface antigen promoter II (SPII) and core promoter (CP) but has no effect on surface antigen promoter I (SPI) or promoter for X gene (Xp). The suppressive effects of HE-145 on either SPII or CP activity is liver-specific, since no suppressive activity of HE-145 was observed when CP or SPII promoter activity was assayed in non-liver cells such as HeLa or 293T. To examine the mode of action of HE-145, EMSA analysis revealed that HE-145 decreased the DNA-binding activity of nuclear extract of HepA2 cells to specific cis element of HBV promoter for core antigen, including peroxisome proliferator-activated receptors (PPARs), PPARs binding site (PPRE), alpha-fetoprotein transcription factor (FTF), and Sp1. Ectopic expression of PPAR gamma or HNF4 alpha partially reversed the HE-145-mediated suppression of HBV RNA. Therefore, HE-145 may represent a novel class of anti-HBV agents which selectively modulate transcriptional machinery of human liver cells to suppress HBV gene expression and replication.
Tseng
Ya Ping
YP
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, ROC.
Kuo
Yueh Hsiung
YH
Hu
Cheng-Po
CP
Jeng
King-Song
KS
Janmanchi
Damodar
D
Lin
Chih Hsiu
CH
Chou
Chen Kung
CK
Yeh
Sheau Farn
SF
D000998:Antiviral Agents / Q000494:pharmacology*; D019677:Artificial Gene Fusion; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D017705:Lignans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding; D014158:Transcription, Genetic / Q000187:drug effects*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014779:Virus Replication / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology*
D000998:Antiviral Agents; D004279:DNA, Viral; D017705:Lignans; D014764:Viral Proteins; D014970:Xanthines; C505802:helioxanthin; D008156:Luciferases