Abstract
Epstein-Barr virus (EBV) LMP1 is a major oncoprotein expressed in latent infection. It functions as a TNFR family member and constitutively activates cellular signals, such as NFκB, MAPK, JAK/STAT and AKT. We here screened small molecule inhibitors and isolated HSP90 inhibitors, Radicicol and 17-AAG, as candidates that suppress LMP1 expression and cell proliferation not only in EBV-positive SNK6 Natural Killer (NK) cell lymphoma cells, but also in B and T cells. Tumor formation in immuno-defficient NOD/Shi-scid/IL-2Rγ(null) (NOG) mice was also retarded. These results suggest that HSP90 inhibitors can be alternative treatments for patients with EBV-positive malignancies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Benzoquinones / chemistry
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Benzoquinones / pharmacology*
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Cell Proliferation / drug effects
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Epstein-Barr Virus Infections / drug therapy*
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Epstein-Barr Virus Infections / genetics
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Epstein-Barr Virus Infections / immunology
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Epstein-Barr Virus Infections / pathology
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Gene Expression Regulation
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / genetics*
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HSP90 Heat-Shock Proteins / immunology
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Herpesvirus 4, Human / drug effects
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Herpesvirus 4, Human / genetics
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Herpesvirus 4, Human / immunology
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Humans
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Immunocompromised Host
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Killer Cells, Natural / pathology
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / pharmacology*
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Lymphoma / drug therapy*
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Lymphoma / genetics
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Lymphoma / immunology
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Lymphoma / pathology
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Macrolides / chemistry
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Macrolides / pharmacology*
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Mice
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Mice, Inbred NOD
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Neoplasms, Experimental
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Signal Transduction
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
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Tumor Burden / drug effects
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Viral Matrix Proteins / antagonists & inhibitors
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Viral Matrix Proteins / genetics*
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Viral Matrix Proteins / immunology
Substances
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Antineoplastic Agents
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Benzoquinones
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EBV-associated membrane antigen, Epstein-Barr virus
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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Macrolides
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Small Molecule Libraries
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Viral Matrix Proteins
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tanespimycin
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monorden
Grants and funding
This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, Culture and Technology (no. 20390137, 21022055 to T. T.), the Ministry of Health, Labour, and Welfare (to T. T. & H. K.) and partly by the Uehara Memorial Research Fund (to T. T. & T. M.), the Takeda Science Foundation (to T. T. & T. M.), the Yasuda Medical Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Senshin Medical Research Foundation, and the Kanae Foundation for Promotion of Medical Science (to T. M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.