PIM 抑制剂 SMI-4a 通过 JAK2/STAT3 通路诱导 B 细胞急性淋巴细胞白血病细胞凋亡和细胞周期停滞,Blood

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PIM 抑制剂 SMI-4a 通过 JAK2/STAT3 通路诱导 B 细胞急性淋巴细胞白血病细胞凋亡和细胞周期停滞
Blood ( IF 21.0 ) Pub Date : 2018-11-29 , DOI: 10.1182/blood-2018-99-117804
Xingyi Kuang ₁ , Jie Xiong ₁ , Weili Wang ₁ , Xinyao Li ₂ , Tingting Lu ₃ , Jishi Wang ₄

Affiliation

丝氨酸/苏氨酸 PIM 蛋白激酶是多种血液系统恶性肿瘤和实体癌肿瘤发生的关键调节剂。我们使用实时荧光定量 PCR 检测 B 细胞急性淋巴细胞白血病 (B-ALL) 患者中 PIM 的表达，发现 B-ALL 患者中 PIM 的表达显着高于正常对照。SMI-4a 是一种泛 PIM 小分子抑制剂，该药物在广泛的血液恶性细胞系中表现出明显的临床前抗肿瘤活性。为了进一步探讨 SMI-4a 对 B-ALL 细胞的影响，将 B-ALL 细胞系 CCRF-SB 和 Sup-B15 用这种小分子抑制剂处理，结果表明 SMI-4a 抑制 B-ALL 细胞增殖剂量和时间依赖性方式。而且，SMI-4a 显着促进 B-ALL 细胞凋亡并导致 G0/G1 期细胞周期停滞。Western blot结果显示，SMI-4a增加了Caspase-3、Caspase-9、Bax和P21的表达，降低了Bcl-2和CDK4的表达。此外，我们发现 SMI-4a 显着抑制 JAK2/STAT3 通路的激活，而 HO-1 干扰 JAK2/STAT3 通路以抑制 SMI-4a 诱导的 ALL 细胞凋亡。最后，在 NOD/SCID 小鼠中进行异种移植实验以研究 SMI-4a 在体内 B-ALL 肿瘤发生中的潜在作用。为了观察 SMI-4a 对体内肿瘤生长的影响，NOD/SCID 小鼠移植 B-ALL 变异细胞，荷瘤小鼠分别腹腔注射生理盐水和 SMI-4a。因此，用 SMI-4a 处理导致对肿瘤生长的显着抑制。此外，PIM抑制剂明显减少了B-ALL细胞来源的肿瘤的体积和重量。TUNEL 检测显示 SMI-4a 处理组的凋亡细胞比例高于对照组。总之，我们的数据显示 PIM 抑制剂 (SMI-4a) 在体外和体内显着抑制 B-ALL 细胞的生长，并促进细胞凋亡和细胞周期停滞。这种抑制作用部分是通过抑制 JAK2/STAT3 通路激活来介导的。披露没有需要申报的相关利益冲突。TUNEL 检测显示 SMI-4a 处理组的凋亡细胞比例高于对照组。总之，我们的数据显示 PIM 抑制剂 (SMI-4a) 在体外和体内显着抑制 B-ALL 细胞的生长，并促进细胞凋亡和细胞周期停滞。这种抑制作用部分是通过抑制 JAK2/STAT3 通路激活来介导的。披露没有需要申报的相关利益冲突。TUNEL 检测显示 SMI-4a 处理组的凋亡细胞比例高于对照组。总之，我们的数据显示 PIM 抑制剂 (SMI-4a) 在体外和体内显着抑制 B-ALL 细胞的生长，并促进细胞凋亡和细胞周期停滞。这种抑制作用部分是通过抑制 JAK2/STAT3 通路激活来介导的。披露没有需要申报的相关利益冲突。

"点击查看英文标题和摘要"

PIM Inhibitor SMI-4a Induces Cell Apoptosis and Cell Cycle Arrest in B-Cell Acute Lymphocytic Leukemia Cells Via the JAK2/STAT3 Pathway

The serine/threonine PIM protein kinases are critical regulators of turmorigenesis in mutiple hematologic malignancies and solid cancers. We used real-time PCR to detect the expression of PIM in B-cell acute lymphocytic leukemia (B-ALL) patients, and found the expression of PIM in B-ALL patients was significantly higher than that in normal controls. SMI-4a is a pan-PIM small molecule inhibitor, and this agent exhibits demonstrable preclinical antitumour activity in a wide range of hematologic malignant cell lines. To further explore the effect of SMI-4a on B-ALL cells, B-ALL cell lines CCRF-SB and Sup-B15 were treated with this small molecule inhibitor, and the results showed that SMI-4a inhibited B-ALL cell proliferation in a dose- and time-dependent manner. Moreover, SMI-4a significantly promoted B-ALL cell apoptosis and caused cell cycle arrest in the G0/G1 phase. The results of Western blot showed that SMI-4a increased the expression of Caspase-3, Caspase-9, Bax and P21, and decreased the expression of Bcl-2 and CDK4. Furthermore, we found that SMI-4a significantly inhibits the activation of the JAK2/STAT3 pathway and HO-1 interferes with the JAK2/STAT3 pathway to inhibit SMI-4a-induced ALL cell apoptosis. Finally, xenograft experiments in NOD/SCID mice were operated to investigate the potential role of SMI-4a in B-ALL tumorigenesis in vivo. To observe the effect of SMI-4a on tumor growth in vivo, NOD/SCID mice were transplanted with B-ALL devied cells, and the tumor-bearing mice were intraperitoneally injected with saline and SMI-4a, respectively. As a result, tretment with SMI-4a resulted in a significant inhibition on tumor growth. In addition, PIM inhibtor obviously reduced the volume and weight of B-ALL cell-derived tumors. TUNEL assay revealed the proportion of apoptotic cells was higher in the SMI-4a-treated group than in the control group. Taken together, our data showed PIM inhibitor (SMI-4a) significantly inhibits the growth of B-ALL cells in vitro and in vivo and promotes apoptosis and cell cycle arrest. This suppressive effect is mediated partly through inhibiting the JAK2/STAT3 pathway activation. Disclosures No relevant conflicts of interest to declare.

更新日期：2018-11-29

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