Epstein-Barr virus RNA confers resistance to interferon-alpha-induced apoptosis in Burkitt's lymphoma.
We investigated whether Epstein--Barr virus (EBV) infection could counteract the antitumor effect of interferon (IFN)-alpha. EBV-negative subclones isolated from EBV-positive Burkitt's lymphoma (BL) cell lines Akata, Daudi and Mutu were found to fall into apoptosis after IFN-alpha treatment. On the other hand, EBV-positive counterparts exhibited striking resistance against IFN-alpha-induced apoptosis. Transfection of an individual EBV latent gene into EBV-negative BL cells revealed that EBV-encoded poly(A)(-) RNAs (EBERs) were responsible for IFN resistance. EBERs bound double-stranded (ds) RNA-activated protein kinase (PKR), a key mediator of the antiviral effect of IFN-alpha, and inhibited its phosphorylation. Transfection of dominant-negative PKR, which was catalytically inactive and could block phosphorylation of endogenous PKR, made EBV-negative BL cells resistant to IFN-alpha-induced apoptosis. Furthermore, EBERs did not bind mutant PKR, which was catalytically active but lacked dsRNA-binding activity, nor did they inhibit its phosphorylation. These results indicate that EBERs confer resistance to IFN-alpha-induced apoptosis via binding to PKR and inhibition of its phosphorylation. This is the first report that the virus counteracts IFN-induced apoptosis in virus-associated tumors.
Nanbo
Asuka
A
Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan.
Inoue
Kaori
K
Adachi-Takasawa
Kumi
K
Takada
Kenzo
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D002472:Cell Transformation, Viral; D002999:Clone Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000821:virology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D024882:Drug Resistance, Viral / Q000502:physiology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000032:analysis; D018390:Gene Targeting; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012330:RNA, Double-Stranded / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000821:virology; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D019309:Epstein-Barr Virus Nuclear Antigens; C099537:Epstein-Barr virus encoded RNA 1; C106732:Epstein-Barr virus encoded RNA 2; D016898:Interferon-alpha; D009363:Neoplasm Proteins; D012330:RNA, Double-Stranded; D012334:RNA, Neoplasm; D012367:RNA, Viral; D019892:eIF-2 Kinase; C417029:EBV-encoded nuclear antigen 1