Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism.
EBV causes infectious mononucleosis and is associated with certain malignancies. EBV nuclear antigen 1 (EBNA1) mediates EBV genome replication, partition, and transcription, and is essential for persistence of the viral genome in host cells. Here we demonstrate that Hsp90 inhibitors decrease EBNA1 expression and translation, and that this effect requires the Gly-Ala repeat domain of EBNA1. Hsp90 inhibitors induce the death of established, EBV-transformed lymphoblastoid cell lines at doses nontoxic to normal cells, and this effect is substantially reversed when lymphoblastoid cell lines are stably infected with a retrovirus expressing a functional EBNA1 mutant lacking the Gly-Ala repeats. Hsp90 inhibitors prevent EBV transformation of primary B cells, and strongly inhibit the growth of EBV-induced lymphoproliferative disease in SCID mice. These results suggest that Hsp90 inhibitors may be particularly effective for treating EBV-induced diseases requiring the continued presence of the viral genome.
Sun
Xiaoping
X
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Barlow
Elizabeth A
EA
Ma
Shidong
S
Hagemeier
Stacy R
SR
Duellman
Sarah J
SJ
Burgess
Richard R
RR
Tellam
Judy
J
Khanna
Rajiv
R
Kenney
Shannon C
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004151:Dipeptides / Q000235:genetics; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D004854:Herpesvirus 4, Human; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D008232:Lymphoproliferative Disorders / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects
D016227:Benzoquinones; D017931:DNA Primers; D004151:Dipeptides; D019309:Epstein-Barr Virus Nuclear Antigens; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin; C065992:N-glycylalanine