Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells

Shotaro Ando, Jun Ichi Kawada, Takahiro Watanabe, Michio Suzuki, Yoshitaka Sato, Yuka Torii, Masato Asai, Fumi Goshima, Takayuki Murata, Norio Shimizu, Yoshinori Ito, Hiroshi Kimura

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15 Citations (Scopus)

Abstract

Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.

Original languageEnglish
Pages (from-to)76793-76805
Number of pages13
JournalOncotarget
Volume7
Issue number47
DOIs
Publication statusPublished - 01-01-2016

All Science Journal Classification (ASJC) codes

  • Oncology

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    Ando, S., Kawada, J. I., Watanabe, T., Suzuki, M., Sato, Y., Torii, Y., Asai, M., Goshima, F., Murata, T., Shimizu, N., Ito, Y., & Kimura, H. (2016). Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells. Oncotarget, 7(47), 76793-76805. https://doi.org/10.18632/oncotarget.12529