The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas

Michio Suzuki, Tadashi Takeda, Hikaru Nakagawa, Seiko Iwata, Takahiro Watanabe, Mohammed N.A. Siddiquey, Fumi Goshima, Takayuki Murata, Jun Ichi Kawada, Yoshinori Ito, Seiji Kojima, Hiroshi Kimura

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Abstract

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.

Original languageEnglish
Article number280
JournalFrontiers in Microbiology
Volume6
Issue numberAPR
DOIs
Publication statusPublished - 01-01-2015

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HSP90 Heat-Shock Proteins
Natural Killer T-Cells
Human Herpesvirus 4
Lymphoma
Growth
Membrane Proteins
NF-kappa B
Apoptosis
Cell Line
Cyclin D3
Phosphatidylinositol 3-Kinase
Small Molecule Libraries
JNK Mitogen-Activated Protein Kinases
Cell Cycle Checkpoints
6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine
Oncogenes
Heterografts
Natural Killer Cells
Cell Cycle
Proteins

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Microbiology (medical)

Cite this

Suzuki, M., Takeda, T., Nakagawa, H., Iwata, S., Watanabe, T., Siddiquey, M. N. A., ... Kimura, H. (2015). The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas. Frontiers in Microbiology, 6(APR), [280]. https://doi.org/10.3389/fmicb.2015.00280
Suzuki, Michio ; Takeda, Tadashi ; Nakagawa, Hikaru ; Iwata, Seiko ; Watanabe, Takahiro ; Siddiquey, Mohammed N.A. ; Goshima, Fumi ; Murata, Takayuki ; Kawada, Jun Ichi ; Ito, Yoshinori ; Kojima, Seiji ; Kimura, Hiroshi. / The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas. In: Frontiers in Microbiology. 2015 ; Vol. 6, No. APR.
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Suzuki, M, Takeda, T, Nakagawa, H, Iwata, S, Watanabe, T, Siddiquey, MNA, Goshima, F, Murata, T, Kawada, JI, Ito, Y, Kojima, S & Kimura, H 2015, 'The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas', Frontiers in Microbiology, vol. 6, no. APR, 280. https://doi.org/10.3389/fmicb.2015.00280

The heat shock protein 90 inhibitor BIIB021 suppresses the growth of T and natural killer cell lymphomas. / Suzuki, Michio; Takeda, Tadashi; Nakagawa, Hikaru; Iwata, Seiko; Watanabe, Takahiro; Siddiquey, Mohammed N.A.; Goshima, Fumi; Murata, Takayuki; Kawada, Jun Ichi; Ito, Yoshinori; Kojima, Seiji; Kimura, Hiroshi.

In: Frontiers in Microbiology, Vol. 6, No. APR, 280, 01.01.2015.

Research output: Contribution to journalArticle

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AU - Suzuki, Michio

AU - Takeda, Tadashi

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AU - Watanabe, Takahiro

AU - Siddiquey, Mohammed N.A.

AU - Goshima, Fumi

AU - Murata, Takayuki

AU - Kawada, Jun Ichi

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AU - Kojima, Seiji

AU - Kimura, Hiroshi

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