The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas.
Epstein-Barr virus (EBV), which infects not only B cells but also T and natural killer (NK) cells, is associated with a variety of lymphoid malignancies. Because EBV-associated T and NK cell lymphomas are refractory and resistant to conventional chemotherapy, there is a continuing need for new effective therapies. EBV-encoded "latent membrane protein 1" (LMP1) is a major oncogene that activates nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and phosphatidylinositol 3-kinase signaling pathways, thus promoting cell growth and inhibiting apoptosis. Recently, we screened a library of small-molecule inhibitors and isolated heat shock protein 90 (Hsp90) inhibitors as candidate suppressors of LMP1 expression. In this study, we evaluated the effects of BIIB021, a synthetic Hsp90 inhibitor, against EBV-positive and -negative T and NK lymphoma cell lines. BIIB021 decreased the expression of LMP1 and its downstream signaling proteins, NF-κB, JNK, and Akt, in EBV-positive cell lines. Treatment with BIIB021 suppressed proliferation in multiple cell lines, although there was no difference between the EBV-positive and -negative lines. BIIB021 also induced apoptosis and arrested the cell cycle at G1 or G2. Further, it down-regulated the protein levels of CDK1, CDK2, and cyclin D3. Finally, we evaluated the in vivo effects of the drug; BIIB021 inhibited the growth of EBV-positive NK cell lymphomas in a murine xenograft model. These results suggest that BIIB021 has suppressive effects against T and NK lymphoma cells through the induction of apoptosis or a cell cycle arrest. Moreover, BIIB021 might help to suppress EBV-positive T or NK cell lymphomas via the down-regulation of LMP1 expression.
Department of Pediatrics, Nagoya University Graduate School of Medicine Nagoya, Japan ; Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Michio
M
Suzuki
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Tadashi
T
Takeda
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Hikaru
H
Nakagawa
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Seiko
S
Iwata
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Takahiro
T
Watanabe
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Mohammed N A
MN
Siddiquey
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Fumi
F
Goshima
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Takayuki
T
Murata
Department of Pediatrics, Nagoya University Graduate School of Medicine Nagoya, Japan.
Jun-Ichi
J
Kawada
Department of Pediatrics, Nagoya University Graduate School of Medicine Nagoya, Japan.
Yoshinori
Y
Ito
Department of Pediatrics, Nagoya University Graduate School of Medicine Nagoya, Japan.
Seiji
S
Kojima
Department of Virology, Nagoya University Graduate School of Medicine Nagoya, Japan.
Hiroshi
H
Kimura
BIIB021; Epstein-Barr virus; LMP1; T and NK cell lymphoma; heat shock protein 90