Abstract
Epstein-Barr virus (EBV) infects B cells, as well as T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoid malignancies. In various tumor cells, mTOR performs an essential function together with Akt with regard to cell growth. We investigated the effects of mTOR inhibitors on EBV-associated T- and NK-cell lymphomas. We investigated the Akt/mTOR activation pathway in EBV-positive and -negative T- and NK-cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3, and KHYG1). We evaluated the antitumor effects of mTOR inhibitors (rapamycin and its analogue, CCI-779) against these cell lines in culture and in a murine xenograft model that was established by subcutaneous injection of SNK6 cells into NOG mice. All EBV-positive and -negative T- and NK-cell lines tested displayed activation of the Akt/mTOR pathway, and treatment with mTOR inhibitors suppressed mTOR activation. The inhibitors induced G1 cell-cycle arrest and inhibited cell proliferation in T- and NK-cell lines. Overall, T cell lines were more sensitive to rapamycin, but there were no significant differences between EBV-positive and -negative cell lines. Treatment with rapamycin did not affect lytic or latent EBV gene expression. Intraperitoneal treatment with CCI-779 significantly inhibited the growth of established tumors in NOG mice and reduced the EBV load in peripheral blood. These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T- and NK-cell lymphoma.
Highlights
Epstein–Barr virus (EBV) is a ubiquitous, oncogenic g-herpes virus that infects up to 95% of the adult population worldwide
These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T- and natural killer (NK)-cell lymphoma
Rapamycin inhibits mTOR signaling in T- and NK-cell lines
Summary
Epstein–Barr virus (EBV) is a ubiquitous, oncogenic g-herpes virus that infects up to 95% of the adult population worldwide. EBV primarily infects B cells, but it can infect T cells and natural killer (NK) cells and has been associated with multiple lymphoid malignancies, including Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, posttransplant lymphoproliferative disorders, nasal NK/T-cell lymphoma, hydroa vacciniforme-like lymphoma, aggressive NK cell leukemia, and chronic active EBV disease [1,2,3]. Treatment of EBV-associated lymphoid malignancies often requires cytotoxic chemotherapies that are not always successful. Clonal antibody against CD20, targets B-cell–specific surface antigens present on EBV-transformed malignant cells. It has recently been used for the treatment and prophylaxis of Bcell lymphoma and lymphoproliferative disorders [4]. There is a continuing need for the effective treatment of T- and NK-cell lymphoid malignancies
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