Chronic myeloid leukaemia: an investigation into the role of Bcr-Abl-induced abnormalities in glucose transport regulation
Chronic myeloid leukaemia: an investigation into the role of Bcr-Abl-induced abnormalities in glucose transport regulation
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DOI：
10.1038/sj.onc.1208461
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发表时间：
2005-05-05
期刊：
影响因子：
8
通讯作者：
Baldwin, SA
中科院分区：
文献类型：
--
作者：
Barnes, K;McIntosh, E;Baldwin, SA
在慢性粒细胞白血病（CML）中，嵌合酪氨酸激酶Bcr-Abl的表达在缺乏IL-3的情况下通过非自分泌机制促进造血干细胞的不适当存活。刺激葡萄糖摄入似乎在正常造血细胞中这种细胞因子抑制细胞凋亡方面发挥重要作用。为了研究癌蛋白和细胞因子介导的细胞存活机制是否有相似之处，我们采用了一种可诱导表达Bcr-Abl的造血细胞系TonB 210，发现酪氨酸激酶在去嘌呤细胞中的表达模拟了IL-3在维持较高的己糖摄取V-max方面的作用。在IL-3处理的细胞和表达Bcr-Abl的细胞中，高己糖摄取率与GLUT 1葡萄糖转运蛋白的总细胞含量的约80%的细胞表面保留相关。相比之下，在不存在IL-3的情况下，用Bcr-Abl激酶抑制剂Glivec（10 μ M）处理表达Bcr-Abl的细胞6小时，导致约90%的细胞表面转运蛋白内化，并显著降低（4.4± 0.9（平均值± s.e.m.，4）倍）的V-max的己糖摄取，没有显着影响的Km为这个过程或总细胞转运蛋白含量。这些作用不是细胞活力的任何显著损失的结果，并且先于由抑制Bcr-Abl引起的凋亡的开始。IL-3处理和Bcr-Abl的表达都导致Akt（蛋白激酶B）的磷酸化增强。IL-3和Bcr-Abl在TonB 210细胞中的运输刺激可被磷脂酰肌醇3激酶抑制剂所抑制，表明该激酶参与了信号转导途径。这些结果表明，葡萄糖转运的抑制在格列卫的治疗作用中起着重要的作用，并且Bcr-Abl参与转运刺激的信号转导途径可能为CML提供新的治疗靶点。
In chronic myeloid leukaemia (CML) expression of the chimeric tyrosine kinase, Bcr-Abl, promotes the inappropriate survival of haemopoietic stem cells by a nonautocrine mechanism in the absence of IL-3. Stimulation of glucose uptake appears to play an important role in the suppression of apoptosis by this cytokine in normal haemopoietic cells. To investigate whether the cell survival mechanisms mediated by the oncoprotein and cytokine showed any similarities, we employed a haemopoietic cell line, TonB210, engineered for inducible expression of Bcr-Abl. Tyrosine kinase expression in cytokine-deprived cells was found to mimic the effect of IL-3 in maintaining a higher V-max for hexose uptake. In both IL-3-treated cells and those expressing Bcr-Abl, high rates of hexose uptake were associated with the retention at the cell surface of approximately 80% of the total cellular content of the GLUT1 glucose transporter. In contrast, treatment of Bcr-Abl-expressing cells for 6 h with the Bcr-Abl kinase inhibitor Glivec (10 μ M), in the absence of IL-3, led to internalization of approximately 90% of the cell-surface transporters and drastically decreased (4.4± 0.9 (mean± s.e.m., 4)-fold) the V-max for hexose uptake, without significant effect on the K-m for this process or on the total cellular transporter content. These effects were not the result of any significant loss in cell viability, and preceded the onset of apoptosis caused by inhibition of Bcr-Abl. Both IL-3 treatment and expression of Bcr-Abl led to enhanced phosphorylation of Akt ( protein kinase B). The stimulation of transport by IL-3 and Bcr-Abl in TonB210 cells was inhibitable by phosphatidylinositol 3-kinase inhibitors, indicating the involvement of this kinase in the signal transduction pathway. These findings suggest that inhibition of glucose transport plays an important role in the therapeutic action of Glivec, and that the signal transduction pathways involved in transport stimulation by Bcr-Abl may offer novel therapeutic targets for CML.