Yiu Stephanie Pei Tung, Hui Kwai Fung, Choi Chung King, Kao Richard Yi Tsun, Ma Chi Wang, Yang Dan, Chiang Alan Kwok Shing
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.
Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong SAR, China.
Cancers (Basel). 2018 Dec 11;10(12):505. doi: 10.3390/cancers10120505.
Pharmaceutical reactivation of lytic cycle of Epstein⁻Barr virus (EBV) represents a potential therapeutic strategy against EBV-associated epithelial malignancies, e.g., gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). A novel lytic-inducing compound, C7, which exhibits structural similarity to Di-2-Pyridyl Ketone 4, 4-Dimethyl-3-Thiosemicarbazone (Dp44mT), a known chelator of intracellular iron, is found to reactivate EBV lytic cycle in GC and NPC. This study aims to investigate the role of intracellular iron chelation by C7 and other iron chelators in lytic reactivation of EBV in GC and NPC. Testing of six structural analogs of C7 revealed only those which have high affinity towards transition metals could induce EBV lytic cycle. Precomplexing C7 and iron chelators to iron prior to treatment of the cells abolished EBV lytic reactivation. Though hypoxia signaling pathway was activated, it was not the only pathway associated with EBV reactivation. Specifically, C7 and iron chelators initiated autophagy by activating extracellular signal-regulated kinase (ERK1/2) to reactivate EBV lytic cycle since autophagy and EBV lytic reactivation were abolished in cells treated with ERK1/2 blockers whilst inhibition of autophagy by 3-Methyladenine (3-MA) and knockdown significantly abolished EBV lytic reactivation. In summary, we discovered a novel mechanism of reactivation of the EBV lytic cycle through intracellular iron chelation and induction of ERK-autophagy axis in EBV-positive epithelial malignancies, raising the question whether clinically available iron chelators can be incorporated into existing therapeutic regimens to treat these cancers.
药物激活爱泼斯坦-巴尔病毒（EBV）的裂解周期是一种针对EBV相关上皮恶性肿瘤（如胃癌（GC）和鼻咽癌（NPC））的潜在治疗策略。一种新型的裂解诱导化合物C7被发现可在GC和NPC中重新激活EBV裂解周期，该化合物与已知的细胞内铁螯合剂二-2-吡啶基酮4,4-二甲基-3-硫代半卡巴腙（Dp44mT）结构相似。本研究旨在探讨C7和其他铁螯合剂通过细胞内铁螯合在GC和NPC中EBV裂解再激活中的作用。对C7的六种结构类似物的测试表明，只有那些对过渡金属具有高亲和力的类似物才能诱导EBV裂解周期。在处理细胞之前将C7和铁螯合剂与铁预先络合可消除EBV裂解再激活。虽然缺氧信号通路被激活，但它不是与EBV再激活相关的唯一途径。具体而言，C7和铁螯合剂通过激活细胞外信号调节激酶（ERK1/2）引发自噬以重新激活EBV裂解周期，因为在用ERK1/2阻滞剂处理的细胞中自噬和EBV裂解再激活被消除，而用3-甲基腺嘌呤（3-MA）抑制自噬和敲低显著消除EBV裂解再激活。总之，我们发现了一种通过细胞内铁螯合和在EBV阳性上皮恶性肿瘤中诱导ERK-自噬轴来重新激活EBV裂解周期的新机制，这就提出了一个问题，即临床上可用的铁螯合剂是否可以纳入现有的治疗方案来治疗这些癌症。
