Contribution of BCR-ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells
Contribution of BCR-ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells
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DOI：
10.1111/j.1349-7006.2009.01365.x
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发表时间：
2010-01-01
期刊：
影响因子：
5.7
通讯作者：
Saito, Hideyuki
中科院分区：
文献类型：
--
作者：
Nambu, Takeru;Araki, Norie;Saito, Hideyuki
BCR-ABL酪氨酸激酶由相互染色体易位t（9;22）产生，导致慢性髓细胞白血病（CML）。BCR-ABL被伊马替尼抑制;然而，已经提出了几种伊马替尼耐药机制，这些机制可以解释伊马替尼在CML患者中的疗效丧失。以前，我们发现外排药物转运蛋白P-糖蛋白的过度表达部分导致伊马替尼耐药的K562 CML细胞没有BCR-ABL突变。为了解释耐药性的另一种机制，我们建立了一个亚克隆（K562/R）的细胞，并检查了这些细胞和野生型K562（K562/W）细胞中的BCR-ABL信号通路。我们发现K562/R细胞对伊马替尼的耐药性是野生型的15倍。在这两种细胞系中，BCR-ABL及其下游信号分子，如ERK 1/2、ERK 5、STAT 5和AKT，在不存在伊马替尼的情况下被磷酸化。在这两种细胞系中，伊马替尼有效地降低了上述所有蛋白的磷酸化，但ERK 1/2除外，有趣的是，ERK 1/2的磷酸化仅在野生型细胞中受到抑制。然后，我们观察到磷酸化ERK 1/2水平在靶向BCR-ABL的siRNA存在下降低，同样，仅在K562/W细胞中。然而，使用ERK 1/2抑制剂U 0126，我们发现我们可以降低K562/R细胞中的磷酸化ERK 1/2水平，并恢复其对伊马替尼的敏感性。综上所述，我们得出结论，BCR-ABL-独立的ERK 1/2激活有助于伊马替尼耐药K562/R细胞，ERK 1/2可能是治疗CML患者的伊马替尼耐药是由于这一机制的目标。（Cancer Sci 2009）。
BCR-ABL tyrosine kinase, generated from the reciprocal chromosomal translocation t(9;22), causes chronic myeloid leukemia (CML). BCR-ABL is inhibited by imatinib; however, several mechanisms of imatinib resistance have been proposed that account for loss of imatinib efficacy in patients with CML. Previously, we showed that overexpression of the efflux drug transporter P-glycoprotein partially contributed to imatinib resistance in imatinib-resistant K562 CML cells having no BCR-ABL mutations. To explain an additional mechanism of drug resistance, we established a subclone (K562/R) of the cells and examined the BCR-ABL signaling pathway in these and wild-type K562 (K562/W) cells. We found the K562/R cells were 15 times more resistant to imatinib than their wild-type counterparts. In both cell lines, BCR-ABL and its downstream signaling molecules, such as ERK1/2, ERK5, STAT5, and AKT, were phosphorylated in the absence of imatinib. In both cell lines, imatinib effectively reduced the phosphorylation of all the above, except ERK1/2, whose phosphorylation was, interestingly, only inhibited in the wild-type cells. We then observed that phospho-ERK1/2 levels decreased in the presence of siRNA targeting BCR-ABL, again, only in the K562/W cells. However, using an ERK1/2 inhibitor, U0126, we found that we could reduce phospho-ERK1/2 levels in K562/R cells and restore their sensitivity to imatinib. Taken together, we conclude that the BCR-ABL-independent activation of ERK1/2 contributes to imatinib resistance in K562/R cells, and that ERK1/2 could be a target for the treatment of CML patients whose imatinib resistance is due to this mechanism. (Cancer Sci 2009).