College of Pharmacy and Cancer Research Institute and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul 01369, Korea.
Int J Mol Sci. 2019 Mar 14;20(6):1286. doi: 10.3390/ijms20061286.
species are known to contain numerous bioactive compounds, including cordycepin. Extracts of (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 which encodes for a key EBV regulator (Zta) of the EBV lytic cycle; finally, we showed that 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.
已知某些物种含有多种具有生物活性的化合物，包括虫草素。虫草素（CME）的提取物因其具有生物活性成分而被用于多种药用目的。虫草素是 CME 的一种活性成分，具有抗增殖、促凋亡和抗炎作用。虫草素在结构上与腺苷不同，其核糖在 3'位缺少一个氧原子。我们之前报道虫草素可抑制 Epstein⁻Barr 病毒（EBV）相关胃癌（EBVaGC）中的 EBV 基因表达和裂解复制。然而，其他研究报道虫草素可诱导 EBV 基因表达和裂解再激活。因此，有必要阐明 CME 生物活性化合物对 EBV 生命周期的生物活性作用。我们首先证实 CME 优先诱导 EBV 基因表达和裂解再激活；其次，确定 CME 中的腺苷诱导 EBV 基因表达和裂解再激活；第三，发现腺苷 A1 受体（ADORA1）是腺苷启动信号通路上调的必需受体，而上调的基因编码 EBV 裂解周期的关键 EBV 调节因子（Zta）；最后，我们表明腺苷引起的上调导致 EBVaGC 异种移植小鼠模型中的肿瘤发展延迟。综上所述，这些结果表明腺苷是一种 EBV 裂解周期诱导物，可抑制 EBVaGC 的发展。
