title: Epstein-Barr virus EBNA2 directs doxorubicin resistance of B cell lymphoma through CCL3 and CCL4-mediated activation of NF-κB and Btk.
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.
authors.affiliation: Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.|Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
authors.forename: Jung Yong
authors.initials: JY
authors.lastname: Hong
authors.affiliation: Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea.
authors.forename: Kung Ju
authors.initials: KJ
authors.lastname: Ryu
authors.affiliation: Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.|Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Chaehwa
authors.initials: C
authors.lastname: Park
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D054405:Chemokine CCL3 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000378:metabolism*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; C402641:EBNA-2 protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D016328:NF-kappa B; D014764:Viral Proteins; D004317:Doxorubicin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: B cell lymphoma; CCL3; CCL4; EBNA2; doxorubicin resistance