Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.
Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.
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DOI：
10.18632/oncotarget.12529
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发表时间：
2016-11-22
期刊：
影响因子：
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通讯作者：
Kimura H
中科院分区：
文献类型：
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作者：
Ando S;Kawada JI;Watanabe T;Suzuki M;Sato Y;Torii Y;Asai M;Goshima F;Murata T;Shimizu N;Ito Y;Kimura H
EB病毒不仅可感染B细胞，还可感染T细胞和自然杀伤(NK)细胞，并与T或NK细胞淋巴瘤有关。这些淋巴系统恶性肿瘤对常规化疗是无效的。我们检测了EBV阳性和阴性B、T和NK细胞系以及EBV相关T细胞淋巴瘤患者的细胞样本中JAK3/STAT5通路的激活情况。然后，我们评估了选择性JAK3抑制剂tofacitinib在体外和小鼠异种移植模型中对这些细胞株的抗肿瘤作用。我们发现，所有EBV阳性的T和NK细胞株以及被测试的患者样本都显示出JAK3/STAT5途径的激活。托法替尼处理后，细胞内磷酸化STAT5水平降低，细胞增殖受到抑制，细胞周期停滞于G1期，EBVLMP1和EBNA1表达降低。EBV阴性的NK细胞系对托法替尼也敏感，而EBV感染的NK细胞系对托法替尼的敏感性高于其亲本系。托法替尼显著抑制NOG小鼠已建立的肿瘤的生长。这些发现表明托法替尼可能是EBV相关T和NK细胞淋巴瘤患者的一种有用的治疗药物。
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.