Departments of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.
Mol Cancer Ther. 2010 Dec;9(12):3302-14. doi: 10.1158/1535-7163.MCT-10-0550.
Phosphorylation of STAT3 on serine 727 regulates gene expression and is found to be elevated in many B-leukemia cells including chronic lymphocytic leukemia (CLL). It is, however, unclear whether targeting STAT3 will be an effective antileukemia therapy. In this study, we assessed in vitro antileukemia activity of the STAT3 inhibitor JSI-124 (cucurbitacin I). JSI-124 potently induces apoptosis in 3 B-leukemia cell lines (BJAB, I-83, and NALM-6) and in primary CLL cells and was associated with a reduction in serine 727 phosphorylation of STAT3. Similarly, knockdown of STAT3 expression induced apoptosis in these leukemia cells. In addition, we found that JSI-124 and knockdown of STAT3 decreased antiapoptotic protein XIAP expression and overexpression of XIAP blocked JSI-124-induced apoptosis. Furthermore, we found that combined treatment of JSI-124 and TRAIL increased apoptosis associated with an increase in death receptor 4 expression. Besides apoptosis, we found that JSI-124 also induced cell-cycle arrest prior to apoptosis in B-leukemia cells. This corresponded with reduced expression of the cell-cycle regulatory gene, cdc-2. Thus, we present here for the first time that JSI-124 induced suppression of serine 727 phosphorylation of STAT3, leading to apoptosis and cell-cycle arrest through alterations in gene transcription in B-leukemia cells.
磷酸化的 STAT3 在丝氨酸 727 上的调节基因表达，并被发现在许多 B 白血病细胞中升高，包括慢性淋巴细胞白血病（CLL）。然而，目前尚不清楚针对 STAT3 是否将是一种有效的抗白血病治疗方法。在这项研究中，我们评估了 STAT3 抑制剂 JSI-124（葫芦素 I）在体外的抗白血病活性。JSI-124 能强烈诱导 3 种 B 白血病细胞系（BJAB、I-83 和 NALM-6）和原发性 CLL 细胞的凋亡，并与 STAT3 的丝氨酸 727 磷酸化减少相关。同样，STAT3 表达的敲低也诱导这些白血病细胞凋亡。此外，我们发现 JSI-124 和 STAT3 的敲低降低了抗凋亡蛋白 XIAP 的表达，而 XIAP 的过表达则阻断了 JSI-124 诱导的凋亡。此外，我们发现 JSI-124 和 TRAIL 的联合治疗增加了与死亡受体 4 表达增加相关的凋亡。除了凋亡，我们还发现 JSI-124 还在 B 白血病细胞中诱导凋亡前的细胞周期停滞。这与细胞周期调节基因 cdc-2 的表达减少相对应。因此，我们在这里首次提出，JSI-124 诱导 STAT3 的丝氨酸 727 磷酸化抑制，导致 B 白血病细胞中的凋亡和细胞周期停滞，通过改变基因转录。
