Abstract
Cordyceps species are known to contain numerous bioactive compounds, including cordycepin. Extracts of Cordyceps militaris (CME) are used in diverse medicinal purposes because of their bioactive components. Cordycepin, one of the active components of CME, exhibits anti-proliferative, pro-apoptotic, and anti-inflammatory effects. Cordycepin structurally differs from adenosine in that its ribose lacks an oxygen atom at the 3′ position. We previously reported that cordycepin suppresses Epstein–Barr virus (EBV) gene expression and lytic replication in EBV-associated gastric carcinoma (EBVaGC). However, other studies reported that cordycepin induces EBV gene expression and lytic reactivation. Thus, it was reasonable to clarify the bioactive effects of CME bioactive compounds on the EBV life cycle. We first confirmed that CME preferentially induces EBV gene expression and lytic reactivation; second, we determined that adenosine in CME induces EBV gene expression and lytic reactivation; third, we discovered that the adenosine A1 receptor (ADORA1) is required for adenosine to initiate signaling for upregulating BZLF1, which encodes for a key EBV regulator (Zta) of the EBV lytic cycle; finally, we showed that BZLF1 upregulation by adenosine leads to delayed tumor development in the EBVaGC xenograft mouse model. Taken together, these results suggest that adenosine is an EBV lytic cycle inducer that inhibits EBVaGC development.
Highlights
Epstein–Barr virus (EBV), is a human gamma-herpesvirus that establishes lifelong infections in more than 95% of the human population [1]
We observed that cordycepin significantly suppressed EBV gene expression and lytic reactivation [15]; and secondly, adenosine deaminase (ADA) converts cordycepin to 3 -deoxyinosine which does not exhibit anti-cancer effects as much as the original cordycepin [16,17,18]
Since CMEs have exhibited anti-tumor and anti-viral activities in several tumor cells [15,21], we verified the anti-viral activities in EBV-associated gastric carcinoma (EBVaGC) using SNU719 cells
Summary
Epstein–Barr virus (EBV), is a human gamma-herpesvirus that establishes lifelong infections in more than 95% of the human population [1]. The EBV genome is maintained as a nuclear episome that replicates once per cell cycle using the host DNA polymerase [7]. Anti-herpesvirus agents exert their effects by either directly inhibiting viral enzymes or disrupting the host-virus interactions [9]. These agents can interfere with viral genome replication, interrupt viral protein synthesis, and modulate the host response to viral infection. We observed that cordycepin significantly suppressed EBV gene expression and lytic reactivation [15]; and secondly, adenosine deaminase (ADA) converts cordycepin to 3 -deoxyinosine which does not exhibit anti-cancer effects as much as the original cordycepin [16,17,18]. We found that the adenosine A1 receptor (ADORA1) is required to upregulate BZLF1, which encodes for a key regulator (Zta) for the EBV lytic cycle
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