Abstract 1252: Intracellular iron chelation by a novel compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle via the ERK-autophagy axis in EBV-positive epithelial cancers

Abstract

Abstract 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 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 6 structural analogues of C7 revealed only those which had high affinity towards transition metals could induce EBV lytic cycle. Pre-complexing 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 autophagy inhibition by 3-MA and ATG5 knockdown significantly abolished EBV lytic reactivation. In summary, we discover a novel mechanism of reactivation of 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 combined with existing therapeutic modalities to treat these cancers. Note: This abstract was not presented at the meeting. Citation Format: Alan K S Chiang, Stephanie PT Yiu, Kwai F. Hui, Chung K. Choi, Richard YT Kao, Dan Yang. Intracellular iron chelation by a novel compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle via the ERK-autophagy axis in EBV-positive epithelial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1252.