Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells
Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells
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DOI：
10.1128/jvi.00690-08
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Brady, John N.
中科院分区：
文献类型：
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作者：
Jung, Kyung-Jin;Dasgupta, Arindam;Brady, John N.
人类T细胞白血病病毒1型（HTLV-1）是侵袭性和致命性疾病成人T细胞白血病的病原体。先前的研究已经证明HTLV-1编码的Tax蛋白通过Tax诱导的NF-κ B途径抑制肿瘤抑制因子p53的功能。鉴于这些属性，我们对小分子抑制剂9-氨基吖啶（9AA）的活性感兴趣，9AA是一种靶向两个重要应激反应途径NF-κ B和p53的抗癌药物。在本研究中，我们研究了9AA对HTLV-1转化细胞的影响。用9AA处理HTLV-1转化的细胞导致细胞活力显著降低。与这些结果相一致，我们观察到在用9AA处理HTLV-1转化的细胞后，亚G细胞的百分比增加，并且通过末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记测定阳性的细胞数量增加。在每个测定中，HTLV-1转化的细胞C8166、Hut 102和MT 2对用9AA处理比对照CEM和外周血单核细胞更敏感。分析p53功能，我们表明，HTLV-1转化细胞与9AA的治疗导致p53蛋白的增加和p53转录活性的激活。重要的是，9AA诱导的细胞死亡可以通过引入p53小干扰RNA来阻断，将p53活性和细胞死亡联系起来。这些结果表明，Tax抑制的p53在HTLV-1转化细胞中的功能是“可用药的”，并且可以通过用9AA处理来恢复。9AA诱导p53并抑制NF-κ B的事实表明了治疗HTLV-1转化细胞的有希望的策略。
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of the aggressive and fatal disease adult T-cell leukemia. Previous studies have demonstrated that the HTLV-1-encoded Tax protein inhibits the function of tumor suppressor p53 through a Tax-induced NF-kappa B pathway. Given these attributes, we were interested in the activity of small-molecule inhibitor 9-aminoacridine (9AA), an anticancer drug that targets two important stress response pathways, NF-kappa B and p53. In the present study, we have examined the effects of 9AA on HTLV-1 -transformed cells. Treatment of HTLV-1-transformed cells with 9AA resulted in a dramatic decrease in cell viability. Consistent with these results, we observed an increase in the percentage of cells in sub-G, and an increase in the number of cells positive by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay following treatment of HTLV-1-transformed cells with 9AA. In each assay, HTLV-1-transformed cells C8166, Hut102, and MT2 were more sensitive to treatment with 9AA than control CEM and peripheral blood mononuclear cells. Analyzing p53 function, we demonstrate that treatment of HTLV-1 -transformed cells with 9AA resulted in an increase in p53 protein and activation of p53 transcription activity. Of significance, 9AA-induced cell death could be blocked by introduction of a p53 small interfering RNA, linking p53 activity and cell death. These results suggest that Tax-repressed p53 function in HTLV-1-transformed cells is "druggable" and can be restored by treatment with 9AA. The fact that 9AA induces p53 and inhibits NF-kappa B suggests a promising strategy for the treatment of HTLV-1-transformed cells.