Imatinib induces mitochondria‐dependent apoptosis of the Bcr‐Abl‐positive K562 cell line and its differentiation toward the erythroid lineage 1
Imatinib induces mitochondria‐dependent apoptosis of the Bcr‐Abl‐positive K562 cell line and its differentiation toward the erythroid lineage 1
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DOI：
10.1096/fj.03-0322
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发表时间：
2003-11
期刊：
影响因子：
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通讯作者：
A. Jacquel;M. Herrant;L. Legros;N. Belhacéne;F. Luciano;G. Pagès;P. Hofman;P. Auberger
中科院分区：
文献类型：
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作者：
A. Jacquel;M. Herrant;L. Legros;N. Belhacéne;F. Luciano;G. Pagès;P. Hofman;P. Auberger
伊马替尼已成为临床开发抗慢性粒细胞白血病的主要化合物。伊马替尼抑制Bcr-Abl的激酶活性，其通过增强造血前体细胞的增殖并保护它们免受凋亡而发挥作用。伊马替尼诱导Bcr-Abl阳性细胞凋亡，但药物如何有效地杀死这些细胞仍然是部分了解。我们在此表明，在K562细胞中，伊马替尼i）消除Bcr-Abl磷酸化和活性，并因此消除Erk 1/2、JNK和AKT活化; ii）诱导线粒体跨膜通透性消散; iii）活化半胱天冬酶3、9和8，表明伊马替尼的作用在线粒体水平上整合;伊马替尼诱导的K562细胞凋亡伴随着红系分化。此外，佛波醇酯抑制伊马替尼诱导的细胞死亡，并促进向巨核细胞谱系分化。最后，我们通过c-DNA阵列分析确定超过20个基因被伊马替尼调节。这些基因参与细胞死亡和分化程序，其中一些基因以前从未报道过表达或参与红细胞分化。我们的研究结果表明，伊马替尼是负责的遗传程序的主要修改，导致死亡和/或分化的K562细胞。
Imatinib has emerged as the lead compound for clinical development against chronic myeloid leukemia. Imatinib inhibits the kinase activity of Bcr-Abl, which functions by enhancing the proliferation of hematopoietic precursors and protecting them against apoptosis. Imatinib induces apoptosis of Bcr-Abl positive cells, but how the drug effectively kills these cells remains partially understood. We show here that in K562 cells imatinib i) abolished Bcr-Abl phosphorylation and activity and as a consequence Erk1/2, JNK, and AKT activation; ii) induced mitochondrial transmembrane permeability dissipation; iii) activated caspases 3, 9, and 8, demonstrating that the effect of imatinib is integrated at the mitochondrial level; and iv) triggered caspase-dependent cleavage of Bcr-Abl. Interestingly, imatinib-mediated apoptosis was accompanied by erythroid differentiation of K562 cells. Moreover, phorbol esters inhibited imatinib-induced cell death and promoted differentiation toward the megakaryocytic lineage. Finally, we determined by c-DNA array analysis that more than 20 genes were modulated by imatinib. These genes are involved in both cell death and differentiation programs, and some of them have never been reported before to be expressed or involved in erythroid differentiation. Our results demonstrate that imatinib is responsible for a major modification of the genetic program resulting in death and/or differentiation of K562 cells.