Duechler M, Shehata M, Schwarzmeier J D, Hoelbl A, Hilgarth M, Hubmann R
Ludwig Boltzmann Institute for Cytokine Research, Medical University Vienna, Vienna, Austria.
Leukemia. 2005 Feb;19(2):260-7. doi: 10.1038/sj.leu.2403592.
Recently, proteasome inhibitors (PI) have attracted interest as novel anticancer agents in B-cell chronic lymphocytic leukemia (B-CLL). A prominent feature of B-CLL cells is the high expression of CD23, which is closely related to cell survival and is regulated by Notch2. Since several components of the Notch signaling cascade are tightly regulated by proteasomal degradation, we studied the effect of PI on Notch2 activity and CD23 expression. Exposure of B-CLL cells to PI led to induction of apoptosis, a time- and dose-dependent downregulation of CD23 expression and a decline in DNA binding of transcriptionally active Notch2. In contrast, the transcription factor NF-AT and its putative target gene CD5, which is highly expressed in B-CLL cells, were unaffected. When the late phase of PI-induced apoptosis was arrested by inhibition of caspase 3, the reduction of Notch2 activity was still observed, indicating that reduction of active Notch2 took place already during an earlier phase of apoptosis. Enforced expression of constitutively active Notch2 decreased PI-mediated apoptosis in a human B-cell line. These data indicate that downregulation of CD23 and loss of Notch2 activity are early steps in PI-induced apoptosis of B-CLL lymphocytes and may be part of the full apoptotic response.
最近，蛋白酶体抑制剂（PI）作为B细胞慢性淋巴细胞白血病（B-CLL）中的新型抗癌药物引起了人们的关注。B-CLL细胞的一个显著特征是CD23的高表达，它与细胞存活密切相关，并受Notch2调控。由于Notch信号级联的几个组分受到蛋白酶体降解的严格调控，我们研究了PI对Notch2活性和CD23表达的影响。将B-CLL细胞暴露于PI会导致细胞凋亡的诱导、CD23表达的时间和剂量依赖性下调以及转录活性Notch2的DNA结合能力下降。相比之下，转录因子NF-AT及其在B-CLL细胞中高表达的假定靶基因CD5未受影响。当通过抑制caspase 3阻止PI诱导凋亡的晚期阶段时，仍观察到Notch2活性的降低，这表明活性Notch2的降低在凋亡的早期阶段就已经发生。组成型活性Notch2的强制表达降低了人B细胞系中PI介导的凋亡。这些数据表明，CD23的下调和Notch2活性的丧失是PI诱导B-CLL淋巴细胞凋亡的早期步骤，可能是完全凋亡反应的一部分。
