title: mTOR inhibitors induce cell-cycle arrest and inhibit tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T- and NK-cell lymphoma.
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kawada
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. yoshi-i@med.nagoya-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Kanazawa
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Mohammed Nure Alam
authors.initials: MN
authors.lastname: Siddiquey
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D020031:Epstein-Barr Virus Infections / Q000150:complications; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D004854:Herpesvirus 4, Human; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000821:virology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000209:etiology / Q000821:virology; D051379:Mice; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus