Bay 11-7082 inhibits transcription factor NF-κB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells
Bay 11-7082 inhibits transcription factor NF-κB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells
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DOI：
10.1182/blood-2002-01-0151
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发表时间：
2002-09-01
期刊：
影响因子：
20.3
通讯作者：
Fujii, M
中科院分区：
文献类型：
--
作者：
Mori, N;Yamada, Y;Fujii, M
人T细胞白血病病毒I型(HTLV-I)是一种侵袭性白血病的病原体，被称为成人T细胞白血病(ATL)。我们先前已经证明，所有感染HTLV-I的T细胞系和来自ATL患者的原代白血病细胞都显示出结构性的高转录因子NF-B-K活性。在这项研究中，我们发现，核因子-kB的抑制剂Bay 11-7082可以诱导HTLV-I感染的T细胞株的凋亡，而对HTLV-I阴性的T细胞的凋亡作用很小。BAY 11-7082能快速有效地降低HTLV-I感染T细胞株中核因子-kB的DNA结合量，并下调受核因子-kB调控的抗凋亡基因Bclx(L)的表达，而对另一转录因子AP-1的DNA结合量影响不大。虽然病毒蛋白TAX是核因子-KB的激活剂，但BAY 11-7082诱导HTLV-I感染细胞的凋亡与TAX表达的减少无关。此外，BAY 11-7082诱导的原代ATL细胞较正常外周血单核细胞的凋亡率更高，且这些细胞的凋亡还与其核因子-kB活性下调有关。我们的结果表明，核因子-kB在HTLV-I感染的白血病细胞的发病和存活中起着关键作用，是预防和治疗ATL的合适靶点。
Human T-cell leukemia virus type I (HTLV-I) Is the causative agent of an aggressive form of leukemia designated adult T-cell leukemia (ATL). We have previously demonstrated that all T-cell lines Infected with HTLV-I and primary leukemic cells from ATL patients display constitutively high activity of transcription factor NF-B-K. In this study we showed that Bay 11-7082, an Inhibitor of NF-KB, Induced apoptosis of HTLV-I-infected T-cell lines but only negligible apoptosis of HTLV-I-negative T cells. Bay 11-7082 rapidly and efficiently reduced the DNA binding of NF-KB In HTLV-I-infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-x(L), regulated by NF-KB, whereas It had little effect on the DNA binding of another transcription factor, AP-1. Although the viral protein Tax Is an activator of NF-KB, Bay 11-7082-induced apoptosis of HTLV-I-infected cells was not associated with reduced expression of Tax. Furthermore, Bay 11-7082-induced apoptosis of primary ATL cells was more prominent than that of normal peripheral blood mononuclear cells, and apoptosis of these cells was also associated with down-regulation of NF-KB activity. Our results Indicate that NF-KB plays a crucial role In the pathogenesis and survival of HTLV-I-infected leukemic cells and that It Is a suitable target for the prevention and treatment of ATL.