Bortezomib induces nuclear translocation of IκBα resulting in gene-specific suppression of NF-κB--dependent transcription and induction of apoptosis in CTCL.
Bortezomib induces nuclear translocation of IκBα resulting in gene-specific suppression of NF-κB--dependent transcription and induction of apoptosis in CTCL.
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DOI：
10.1158/1541-7786.mcr-10-0368
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发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Vancurova I
中科院分区：
文献类型：
--
作者：
Juvekar A;Manna S;Ramaswami S;Chang TP;Vu HY;Ghosh CC;Celiker MY;Vancurova I
皮肤T细胞淋巴瘤是以核因子κB的结构性激活为特征的疾病，它在皮肤T细胞淋巴瘤细胞的存活和抗凋亡中起着至关重要的作用。蛋白酶体抑制剂Bortezomib可抑制CTCL中的NFκB活性，但其作用机制尚不清楚。在这项研究中，我们研究了Bortezomib抑制CTCL Hut-78细胞中NFκB活性的机制。我们证明了Bortezomib和MG132通过诱导核转位和IκBα积聚的新机制抑制了HUT-78细胞中的NFκB活性，IκBα然后与细胞核中的NFκB p65和p50结合并抑制NFκBDNA结合活性。然而，令人惊讶的是，虽然依赖于NFκB的抗凋亡基因CIAP1和CIAP2的表达被硼替佐米抑制，但Bcl2的表达并没有受到抑制。染色质免疫沉淀结果表明，cIAP1和cIAP2启动子主要由NFκB p65/50异源二聚体占据，而bcl2启动子主要由p50/50同源二聚体占据。总之，我们的数据揭示了Bortezomib在CTCL中作用的新机制，并表明Bortezomib抑制依赖于NFκB的基因表达是基因特异性的，并且依赖于招募到NFκB反应启动子的NFκB二聚体的亚基组成。
Cutaneous T cell lymphoma (CTCL) is characterized by constitutive activation of NFκB, which plays a crucial role in the survival of CTCL cells and their resistance to apoptosis. NFκB activity in CTCL is inhibited by the proteasome inhibitor bortezomib; however, the mechanisms remained unknown. In this study, we investigated mechanisms by which bortezomib suppresses NFκB activity in CTCL Hut-78 cells. We demonstrate that bortezomib and MG132 suppress NFκB activity in Hut-78 cells by a novel mechanism that consists of inducing nuclear translocation and accumulation of IκBα, which then associates with NFκB p65 and p50 in the nucleus and inhibits NFκB DNA binding activity. Surprisingly, however, while expression of NFκB-dependent anti-apoptotic genes cIAP1 and cIAP2 is inhibited by bortezomib, expression of Bcl-2 is not suppressed. Chromatin immunoprecipitation indicated that cIAP1 and cIAP2 promoters are occupied by NFκB p65/50 heterodimers, while Bcl-2 promoter is occupied predominantly by p50/50 homodimers. Collectively, our data reveal a novel mechanism of bortezomib function in CTCL and suggest that the inhibition of NFκB-dependent gene expression by bortezomib is gene specific and depends on the subunit composition of NFκB dimers recruited to NFκB-responsive promoters.