過去的研究發現：癌症細胞和病毒感染都會增強細胞對麩醯胺酸的攝取，而且需要麩醯胺酸代謝來提供生物材料以及生物能量，以利癌症細
胞和病毒的複製。已知Rta 所誘導的EB 病毒再活化需要一些細胞因子來協助，而其中有些細胞因子與代謝相關，根據這些線索，我們想知道EB病毒再活化時是否也會增強麩醯胺酸代謝，以及麩醯胺酸代謝是否對於EB 病毒再活化扮演著重要的角色。首先我們發現在EB 病毒再活化時細胞內的麩醯胺酸以及2-氧代戊二酸含量上升。使用SLC1A5 抑制劑可以抑制細胞內增加的麩醯胺酸以及2-氧代戊二酸含量，雖然EB 病毒再活化時麩醯胺酸轉運子SLC1A5 的蛋白質表現量並沒有隨著EB病毒再活化而增加。進一步地使用SLC1A5 抑制劑或麩醯胺酸分解酶抑制劑都可以有效降低EB 病毒裂解期蛋白質或mRNA 的表現量。總結上述發現，可以知道在EB 病毒進入再活化時會增強並需要麩醯胺酸代謝來幫助病毒裂解期的基因轉錄。EB 病毒再活化已知會促使癌症惡化，因此推測以麩醯胺酸代謝作為標的的藥物，將有利於EB 病毒相關癌症的治療以及避免其再度復發。

Previous studies have revealed that glutamine metabolism is important for various virus infections because of its contribution to energy refilling and protein/lipid synthesis. However, the roles of glutamine metabolism in the switch of viral latent infection into lytic
reactivation remain largely unknown. For reactivation of Epstein-Barr virus (EBV), two early critical points are initial mutual induction of immediate early genes (Rta and Zta) and subsequent amplified transcription of downstream genes (EA-D for example). In this study, we tested whether glutamine metabolism is modulated by and required for the early steps of EBV reactivation. Two EBV reactivation models were used here: BCR crosslinking-triggered induction of endogenous Rta/Zta/EA-D in Akata B cells, and ectopic Rta-triggered induction of endogenous Zta/EA-D in TW01-ERGV NPC cells. In both models, we detected an early increase of intracellular glutamine and its downstream metabolites in the cells undergoing EBV reactivation, but not in the EBV-negative control cells treated with same lytic triggers. Our preliminary data suggested that the intracellular glutamine increase is attributed to a glutamine transporter SLC1A5 though EBV
reactivation does not affect its total protein level. Notably, treatment with SLC1A5 blockers (GPNA and BenSer) or with a glutaminase inhibitor (CB-839) significantly
reduced protein levels of endogenous early EBV genes (Zta and EA-D), and EA-D mRNA was also decreased. Therefore, glutamine metabolism is not only enhanced at the initial
step of EBV reactivation but also required for transcription of lytic genes before viral DNA replication and virion production. Since aberrant EBV reactivation is linked to high risk and poor prognosis of EBV-associated cancers, modulation of glutamine metabolism could be a novel therapeutic strategy.

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