Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
Cancer Sci. 2010 May;101(5):1204-11. doi: 10.1111/j.1349-7006.2010.01499.x. Epub 2010 Jan 19.
Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle. We have shown previously that Aurora A expression is increased aberrantly in human T-cell leukemia virus type 1 (HTLV-1)-infected T-cell lines and primary adult T-cell leukemia cells, and a pan-Aurora kinase inhibitor, which inhibits both Aurora A and Aurora B kinases, reduces viability and induces apoptosis in these cells. However, the specific effects of Aurora A inhibition on HTLV-1-infected T-cells are poorly understood. In this study, we addressed this question by comparing the effects of MLN8237, a selective inhibitor of Aurora A, on cell viability, cell cycle progression, and induction of apoptosis in HTLV-1-infected and -uninfected T-cell lines. MLN8237 reduced the viability of HTLV-1-infected T-cell lines within 24 h, but its effects on that of HTLV-1-uninfected T-cell lines were moderate. MLN8237 induced early apoptosis of HTLV-1-infected T-cell lines without induction of polyploidy. It induced p53 and p21 expression in HTLV-1-infected but not in -uninfected T-cell lines, suggesting that MLN8237-treated HTLV-1-infected T-cell lines exit from mitosis and activate a p53-dependent postmitotic G(1) checkpoint, leading to G(1) arrest followed by the induction of apoptosis. Our results suggest that specific inhibition of Aurora A kinase is a potentially useful therapeutic strategy in the treatment of adult T-cell leukemia and that further in vivo exploration is warranted.
极光激酶 A 在有丝分裂纺锤体的正确组装和功能中起着至关重要的作用。我们之前已经表明，人 T 细胞白血病病毒 1（HTLV-1）感染的 T 细胞系和原代成人 T 细胞白血病细胞中异常增加了极光激酶 A 的表达，一种泛极光激酶抑制剂，它可以抑制极光 A 和极光 B 激酶，降低这些细胞的活力并诱导其凋亡。然而，极光 A 抑制对 HTLV-1 感染 T 细胞的具体影响还知之甚少。在这项研究中，我们通过比较 MLN8237（一种选择性的极光激酶 A 抑制剂）对 HTLV-1 感染和未感染的 T 细胞系的细胞活力、细胞周期进程和诱导凋亡的影响来解决这个问题。MLN8237 在 24 小时内降低了 HTLV-1 感染的 T 细胞系的活力，但对 HTLV-1 未感染的 T 细胞系的影响是适度的。MLN8237 诱导 HTLV-1 感染的 T 细胞系早期凋亡，而不诱导多倍体形成。它诱导 HTLV-1 感染的 T 细胞系而不是未感染的 T 细胞系中 p53 和 p21 的表达，这表明 MLN8237 处理的 HTLV-1 感染的 T 细胞系退出有丝分裂并激活 p53 依赖性有丝分裂后 G1 检查点，导致 G1 期阻滞，随后诱导凋亡。我们的结果表明，极光激酶 A 激酶的特异性抑制可能是治疗成人 T 细胞白血病的一种有用的治疗策略，值得进一步进行体内探索。
