// Joo Hyun Kim 1 , Won Seog Kim 1, 2 , Jung Yong Hong 3 , Kung Ju Ryu 4 , Seok Jin Kim 1, 2 , Chaehwa Park 1 1 Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea 2 Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea 3 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea 4 Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea Correspondence to: Won Seog Kim, email: email@example.com Chaehwa Park, email: firstname.lastname@example.org Keywords: EBNA2, CCL3, CCL4, doxorubicin resistance, B cell lymphoma Received: July 22, 2016 Accepted: December 01, 2016 Published: December 27, 2016 ABSTRACT Epstein-Barr virus (EBV)-encoded nuclear antigen, EBNA2, expressed in EBV-infected B lymphocytes is critical for lymphoblastoid cell growth. Microarray profiling and cytokine array screening revealed that EBNA2 is associated with upregulation of the chemokines CCL3 and CCL4 in lymphoma cells. Depletion or inactivation of CCL3 or CCL4 sensitized DLBCL cells to doxorubicin. Our results indicate that EBV influences cell survival via an autocrine mechanism whereby EBNA2 increases CCL3 and CCL4, which in turn activate the Btk and NF-κB pathways, contributing to doxorubicin resistance of B lymphoma cells. Western blot data further confirmed that CCL3 and CCL4 direct activation of Btk and NF-κB. Based on these findings, we propose that a pathway involving EBNA2/Btk/NF-κB/CCL3/CCL4 plays a key role in doxorubicin resistance, and therefore, inhibition of specific components of this pathway may sensitize lymphoma cells to doxorubicin. Evaluation of the relationship between CCL3 expression and EBV infection revealed high CCL3 levels in EBV-positive patients. Our data collectively suggest that doxorubicin treatment for EBNA2-positive DLBCL cells may be effectively complemented with a NF-κB or Btk inhibitor. Moreover, evaluation of the CCL3 and CCL4 levels may be helpful for selecting DLBCL patients likely to benefit from doxorubicin treatment in combination with the velcade or ibrutinib.
Kim, J. H., Kim, W. S., Hong, J. Y., Ryu, K., Kim, S. J., & Park, C. (2017). Epstein-Barr virus EBNA2 directs doxorubicin resistance of B cell lymphoma through CCL3 and CCL4-mediated activation of NF-κB and Btk. Oncotarget, 8(3). https://doi.org/10.18632/oncotarget.14243