Identification of Novel Small Organic Compounds with Diverse Structures for the Induction of Epstein-Barr Virus (EBV) Lytic Cycle in EBV-Positive Epithelial Malignancies.
Identification of Novel Small Organic Compounds with Diverse Structures for the Induction of Epstein-Barr Virus (EBV) Lytic Cycle in EBV-Positive Epithelial Malignancies.
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鉴定具有多种结构的新型小有机化合物，以诱导EBV阳性上皮性恶性肿瘤中爱泼斯坦 - 巴尔病毒（EBV）裂解周期。
DOI：
10.1371/journal.pone.0145994
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chiang AK
中科院分区：
文献类型：
--
作者：
Choi CK;Ho DN;Hui KF;Kao RY;Chiang AK
Phorbol酯是蛋白激酶C （PKC）激活剂，而组蛋白去乙酰化酶（HDAC）抑制剂可引起细胞蛋白乙酰化增强，它们是eb病毒（EBV）潜伏感染细胞中通过PKC途径作用的eb病毒（EBV）裂解周期的主要化学诱导剂。通过其他细胞途径诱导EBV裂解周期的化学诱导剂可能有助于确定导致裂解周期再激活的机制，并提高细胞对裂解诱导的反应性。我们对50,240种新型小有机化合物的化学文库进行了表型筛选，以鉴定胃癌（GC）和鼻咽癌（NPC）细胞中EBV裂解周期的新型强诱导剂。经过连续三轮日益严格的筛选，选出了五种命中目标的化合物。这五种化合物在结构上彼此不同，与磷酸酯或HDAC抑制剂不同。在它们的工作浓度下，它们既不会引起组蛋白的超乙酰化，也不会引起PKC的显著激活，这表明它们的生物学作用模式与已知的化学诱导剂不同。进一步研究了其中两种具有快速溶出诱导作用的化合物诱导EBV溶出循环的机制。与HDAC抑制剂不同，这两种化合物的裂解诱导不受PKCδ特异性抑制剂rottlerin的抑制。有趣的是，这两种化合物都可以与HDAC抑制剂合作，增强EBV阳性上皮癌细胞的EBV裂解周期诱导，为开发提高细胞对裂解再激活的反应性的策略铺平了道路。其中一种化合物与铁螯合剂结构相似，另一种强烈激活MAPK通路。这些结构多样的新型有机化合物可能代表了潜在的新型化学物质，可用于研究导致EBV裂解循环从潜伏期重新激活的任何替代机制。
Phorbol esters, which are protein kinase C (PKC) activators, and histone deacetylase (HDAC) inhibitors, which cause enhanced acetylation of cellular proteins, are the main classes of chemical inducers of Epstein-Barr virus (EBV) lytic cycle in latently EBV-infected cells acting through the PKC pathway. Chemical inducers which induce EBV lytic cycle through alternative cellular pathways may aid in defining the mechanisms leading to lytic cycle reactivation and improve cells’ responsiveness towards lytic induction. We performed a phenotypic screening on a chemical library of 50,240 novel small organic compounds to identify novel class(es) of strong inducer(s) of EBV lytic cycle in gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Five hit compounds were selected after three successive rounds of increasingly stringent screening. All five compounds are structurally diverse from each other and distinct from phorbol esters or HDAC inhibitors. They neither cause hyperacetylation of histone proteins nor significant PKC activation at their working concentrations, suggesting that their biological mode of action are distinct from that of the known chemical inducers. Two of the five compounds with rapid lytic-inducing action were further studied for their mechanisms of induction of EBV lytic cycle. Unlike HDAC inhibitors, lytic induction by both compounds was not inhibited by rottlerin, a specific inhibitor of PKCδ. Interestingly, both compounds could cooperate with HDAC inhibitors to enhance EBV lytic cycle induction in EBV-positive epithelial cancer cells, paving way for the development of strategies to increase cells’ responsiveness towards lytic reactivation. One of the two compounds bears structural resemblance to iron chelators and the other strongly activates the MAPK pathways. These structurally diverse novel organic compounds may represent potential new classes of chemicals that can be used to investigate any alternative mechanism(s) leading to EBV lytic cycle reactivation from latency.