Abstract
Andrographolide is the principal bioactive chemical constituent of Andrographis paniculata and exhibits activity against several viruses, including Epstein–Barr virus (EBV). However, the particular mechanism by which andrographolide exerts an anti-EBV effect in EBV-associated gastric cancer (EBVaGC) cells remains unclear. We investigated the molecular mechanism by which andrographolide inhibits lytic reactivation of EBV in EBVaGC cells (AGS-EBV cell line) using proteomics and bioinformatics approaches. An andrographolide treatment altered EBV protein-expression patterns in AGS-EBV cells by suppressing the expression of EBV lytic protein. Interestingly cellular transcription factors (TFs), activators for EBV lytic reactivation, such as MEF2D and SP1, were significantly abolished in AGS-EBV cells treated with andrographolide and sodium butyrate (NaB) compared with NaB-treated cells. In contrast, the suppressors of EBV lytic reactivation, such as EZH2 and HDAC6, were significantly up-regulated in cells treated with both andrographolide and NaB compared with NaB treatment alone. In addition, bioinformatics predicted that HDAC6 could interact directly with MEF2D and SP1. Furthermore, andrographolide significantly induced cell cytotoxicity and apoptosis of AGS-EBV cells by induction of apoptosis-related protein expression. Our results suggest that andrographolide inhibits EBV lytic reactivation by inhibition of host TFs, partially through the interaction of HDAC6 with TFs, and induces apoptosis of EBVaGC cells.
Highlights
Epstein–Barr virus (EBV) is a ubiquitous gamma-herpesvirus and is strongly associated with the development of several human cancers, including Burkitt’s lymphoma (BL), Hodgkin’s lymphoma, nasopharyngeal carcinoma (NPC), and EBV-associated gastric cancer (EBVaGC)
Because we wished to examine the effect of andrographolide on the inhibition of EBV lytic reactivation, we6 of 16 analyzed further the proteins unique to cells treated with andrographolide and NaB
We found that the expression of CREB3L2, MEF2D, specificity protein 1 (SP1), XBP1 and XPB was decreased in AGS-EBV cells treated with the combination of andrographolide and NaB compared with NaB treatment alone
Summary
EBV is a ubiquitous gamma-herpesvirus and is strongly associated with the development of several human cancers, including Burkitt’s lymphoma (BL), Hodgkin’s lymphoma, nasopharyngeal carcinoma (NPC), and EBVaGC. EBVaGC is a subtype of gastric adenocarcinoma (GC) and accounts for approximately 10% of all GCs. EBV establishes two alternative modes of infection in the host cell, latent and lytic infection. Latent infection plays an essential role in carcinogenesis through the activities of latent-stage proteins, especially LMP1. Upon reactivation induced by various stimuli, EBV undergoes three consecutive lytic stages, the immediate early (IE), early (E), and late (L) stages. The IE proteins, Zta and Rta, activate transcription from the promoters of E genes, which trigger
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