A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein β and NF-κB activity in Hodgkin and anaplastic large cell lymphomas
A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein β and NF-κB activity in Hodgkin and anaplastic large cell lymphomas
复制标题
DOI：
10.1182/blood-2004-11-4513
复制
发表时间：
2005-09-01
期刊：
影响因子：
20.3
通讯作者：
Dörken, B
中科院分区：
文献类型：
--
作者：
Jundt, F;Raetzel, N;Dörken, B
免疫抑制性大环内酯类雷帕霉素及其衍生物依维莫司（SDZ RAD，RAD）抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。在这项研究中，我们提供的证据表明，RAD具有深刻的抗增殖活性在体外和NOD/SCID小鼠在体内对霍奇金淋巴瘤（HL）和间变性大细胞淋巴瘤（ALCL）细胞。此外，我们确定了2个分子机制，显示RAD如何发挥抗增殖作用的HL和ALCL细胞。RAD下调转录因子CCAAT增强子结合蛋白β（C/ EBP β）的截短亚型，已知其破坏终末分化并诱导转化表型。此外，RAD抑制组成性核因子-κ B（NF-κ B）的活性，这是HL细胞的关键存活因子。因此，RAD对mTOR通路的药理学抑制干扰HL和ALCL细胞中的基本增殖和存活通路，并可能作为一种新的治疗选择。
The immunosuppressive macrolide rapamycin and its derivative everolimus (SDZ RAD, RAD) inhibit the mammalian target of rapamycin (mTOR) signaling pathway. In this study, we provide evidence that RAD has profound antiproliferative activity in vitro and in NOD/SCID mice in vivo against Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) cells. Moreover, we identified 2 molecular mechanisms that showed how RAD exerts antiproliferative effects in HL and ALCL cells. RAD down-regulated the truncated isoform of the transcription factor CCAAT enhancer binding protein beta (C/ EBP beta), which is known to disrupt terminal differentiation and induce a transformed phenotype. Furthermore, RAD inhibited constitutive nuclear factor kappa B (NF-kappa B) activity, which is a critical survival factor of HL cells. Pharmacologic inhibition of the mTOR pathway by RAD therefore interferes with essential proliferation and survival pathways in HL and ALCL cells and might serve as a novel treatment option.