Proteasome inhibition drastically but reversibly impairs murine lymphocyte development
Proteasome inhibition drastically but reversibly impairs murine lymphocyte development
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DOI：
10.1038/sj.cdd.4402297
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发表时间：
2008-03-01
影响因子：
12.4
通讯作者：
Voll, R. E.
中科院分区：
文献类型：
--
作者：
Maseda, D.;Meister, S.;Voll, R. E.
蛋白酶体抑制剂硼替佐米可诱导各种癌细胞系（包括淋巴瘤）的细胞死亡，最近已被批准用于治疗复发性多发性骨髓瘤。蛋白酶体转运蛋白介导的肿瘤细胞死亡的重要机制是抑制NF-κ B活化和诱导末端未折叠蛋白反应（UPR）。然而，关于硼替佐米对发育和成熟淋巴细胞的影响知之甚少。因此，Balb/C小鼠注射硼替佐米并分析淋巴细胞亚群。这种处理导致T和B淋巴细胞前体的数量显著减少，而成熟淋巴细胞仅受到部分影响。在单次硼替佐米注射后3天，胸腺细胞几乎耗尽，pro-B和pre-B细胞在2天后已经耗尽。2周内胸腺细胞和B细胞前体恢复。发育中淋巴细胞数量的减少是由于凋亡性细胞死亡伴随着强烈增加的半胱天冬酶3/7活性。在注射硼替佐米后8 h内，骨髓B细胞中热休克蛋白70和C/EBP同源蛋白的诱导分别强烈地表明内质网应激和末端UPR的激活。因此，通过蛋白酶体抑制诱导细胞凋亡可以显著影响淋巴细胞发育，这一事实对硼替佐米的临床应用具有重要意义，特别是在淋巴细胞生成持续的情况下。
The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitor-mediated tumor cell death are the inhibition of NF-kappa B activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.