Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells
Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells
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DOI：
10.1038/leu.2008.95
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发表时间：
2008-05-01
期刊：
影响因子：
11.4
通讯作者：
Cuvillier, O.
中科院分区：
文献类型：
--
作者：
Bonhoure, E.;Lauret, A.;Cuvillier, O.
我们研究了调节神经酰胺/鞘氨醇-1-磷酸平衡的鞘氨醇激酶-1(SphK1)在敏感或耐药的慢性髓系白血病细胞对伊马替尼的易感性中的作用。伊马替尼敏感的LAMA84-S表现出明显的SphK1抑制作用，同时神经酰胺含量增加，促存活的鞘氨醇-1-磷酸减少。反之，伊马替尼对LAMA84-r的鞘脂代谢没有影响。用法尼基转移酶或MEK/ERK抑制剂以及阿糖胞苷克服LAMA84-r对伊马替尼的耐药性会导致SphK1抑制。在LAMA84-S细胞中过表达SphK1可通过调节Bim、Bclxl和Mcl-1的表达来抑制伊马替尼对Caspase-3活化、细胞色素c和Smac从线粒体释放的影响，从而损害细胞的凋亡。用F-12509a药理抑制SphK1或用siRNA沉默SphK1可诱导伊马替尼敏感和耐药细胞的凋亡，提示抑制SphK1在细胞凋亡信号转导中起关键作用。我们还表明，F-12509a抑制剂在体外可以成功地杀死慢性粒细胞白血病患者对伊马替尼敏感和耐药的原代细胞。这些结果揭示了SphK1参与调节伊马替尼诱导的细胞凋亡，并证实SphK1是被伊马替尼抑制的BcrAbl/RAS/ERK通路的下游效应因子，但却是Bcl2家族成员的上游调节因子。
We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and-resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and-resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the BcrAbl/ Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members.