Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1
Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1
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DOI：
10.1111/j.1349-7006.2008.01038.x
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发表时间：
2009-02-01
期刊：
影响因子：
5.7
通讯作者：
Ueda, Ryuzo
中科院分区：
文献类型：
--
作者：
Ri, Masaki;Iida, Shinsuke;Ueda, Ryuzo
Bortezomib是一种蛋白酶体抑制剂，最初是作为核因子-kappa B途径的抑制剂而开发的，目前用于治疗多发性骨髓瘤(MM)和套细胞淋巴瘤(MCL)。这种抗肿瘤药物的作用机制已经被几个研究人员研究过了。在此，我们从线粒体膜损伤的水平探讨了硼替佐米诱导皮肤T细胞淋巴瘤(CTCL)和成人T细胞白血病/淋巴瘤(ATLL)细胞凋亡的潜在机制。在包括KMS-12-PE[MM]、HUT78[CTCL]、ATN1[ATLL]和MT4[ATLL]在内的所有细胞系中，经Bortezomib处理后，c-Flip和XIAP等抗凋亡因子表达下调，可能是通过抑制核因子-kappa B信号转导而实现的。此外，在仅BH3家族的成员中，在接触Bortezomib后，Noxa在转录和蛋白质水平上的上调一直是以P53不依赖的方式被观察到。小干扰RNA对NOXA的抑制作用部分挽救了CTCL和ATLL细胞对硼替佐米诱导的细胞凋亡的作用。免疫沉淀实验表明，在所有类型的细胞中，Noxa和Mcl-1呈时间依赖性结合，提示Mcl-1的功能抑制导致线粒体外膜电位的丧失。在ATLL患者的原发肿瘤细胞中也得到了类似的结果。综上所述，我们得出结论，硼替佐米诱导ATLL和CTCL细胞的凋亡至少部分依赖于NoxA的上调和Mcl-1的功能抑制，在MM和恶性黑色素瘤中也是如此。(《癌症科学》2009；100：341-348)。
Bortezomib, a proteasome inhibitor that was originally developed as an inhibitor of nuclear factor-kappa B pathways, is currently used for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). The mechanisms of action of this antitumor agent have been studied by several investigators. Here, we explore the underlying mechanisms of bortezomib-induced apoptosis in cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATLL) at the level of mitochondrial membrane injury. In all cell lines including (KMS-12-PE [MM], HUT78 [CTCL], ATN1 [ATLL], and MT4 [ATLL]), antiapoptotic factors such as c-Flip and XIAP were downregulated after exposure to bortezomib, probably via inhibition of nuclear factor-kappa B signaling. In addition, among the members of the BH3-only family, upregulation of Noxa was consistently seen at both the transcriptional and protein levels in a p53-independent manner after exposure to bortezomib. Repression of Noxa by small interfering RNA partially rescued CTCL and ATLL cells from bortezomib-induced apoptosis. Immunoprecipitation assays indicated time-dependent binding of Noxa and Mcl-1 in all cell types, suggesting that functional repression of Mcl-1 led to the loss of mitochondrial outer membrane potential. Similar results were also obtained in primary tumor cells from patients with ATLL. Taken together, we conclude that bortezomib-induced apoptosis in ATLL and CTCL cells at least partly depends on the upregulation of Noxa and functional repression of Mcl-1, as is also the case in MM and malignant melanoma. (Cancer Sci 2009; 100: 341-348).