The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways
The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways
复制标题
DOI：
10.1182/blood-2008-09-177881
复制
发表时间：
2009-11-12
期刊：
影响因子：
20.3
通讯作者：
Grant, Steven
中科院分区：
文献类型：
--
作者：
Rahmani, Mohamed;Anderson, Anh;Grant, Steven
研究了丝裂原活化蛋白激酶/细胞外信号调节激酶1/2(MEK/ERK1/2)和磷脂酰肌醇3-激酶(PI3K/Akt)同时阻断诱导白血病细胞凋亡的机制。使用MEK抑制剂PD184352或U0126和PI3K/Akt抑制剂Perifosine抑制这些途径可显著诱导多种恶性人类造血细胞的凋亡，并显著降低原发急性髓细胞白血病的集落形成能力，但不能降低正常CD34(+)细胞的集落形成能力。这些事件与显著的Bim上调，Mcl-1下调，显著的Bak/Bax构象改变伴随Bax膜转位，以及Bax/Bak结合显著增加有关。利用TET诱导的Akt、固有活性的MEK1、显性负性Akt和MEK1小干扰RNA的分子研究表明，MEK/ERK1/2和Akt通路的抑制在Perifosine/PD184352介导的致死中起关键作用。异位Mcl-1的表达能有效地抑制Perifosine/PD184352诱导的细胞凋亡，Bak或Bax基因敲除也是如此。值得注意的是，敲除Bim而不是Bad，阻止了Bak和Bax的构象变化，抑制了Bax膜的转位，减少了Bax/Bak的结合，并显著减弱了Perifosine/PD184352诱导的细胞凋亡。最后，增强表达Bim可显著增强PI3K/Akt抑制剂诱导的细胞凋亡，类似于MEK1/2抑制剂的作用。总而言之，这些发现表明，Bim和Mcl-1，但不是Bad，整合了由人类白血病细胞中PI3K/Akt和MEK1/2/ERK1/2通路的伴随中断而触发的死亡信号。(Blod.2009；114：4507-4516)
Mechanisms underlying apoptosis induced by concomitant interruption of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways were investigated in human leukemia cells. Inhibition of these pathways using the MEK inhibitor PD184352 or U0126 and the PI3K/Akt inhibitor perifosine strikingly induced apoptosis in multiple malignant human hematopoietic cells, and substantially reduced the colony-forming capacity of primary acute myeloblastic leukemia, but not normal CD34(+) cells. These events were associated with pronounced Bim up-regulation, Mcl-1 down-regulation, marked Bak/Bax conformational change accompanied by Bax membrane translocation, and a pronounced increase in Bax/Bak association. Molecular studies using tet-inducible Akt, constitutively active MEK1, dominant-negative Akt, and MEK1 small interfering RNA revealed that inhibition of both MEK/ERK1/2 and Akt pathways plays a critical functional role in perifosine/PD184352-mediated lethality. Ectopic Mcl-1 expression potently inhibited perifosine/PD184352-induced apoptosis, as did Bak or Bax knockdown. Notably, knockdown of Bim, but not Bad, blocked Bak and Bax conformational change, inhibited Bax membrane translocation, diminished Bax/Bak binding, and sharply attenuated perifosine/PD184352 induced apoptosis. Finally, enforced expression of Bim significantly enhanced apoptosis induced by PI3K/Akt inhibitors, analogous to the effects of MEK1/2 inhibitors. Collectively, these findings suggest that Bim, and Mcl-1, but not Bad, integrate death signaling triggered by concomitant disruption of the PI3K/Akt and MEK1/2/ERK1/2 pathways in human leukemia cells. (Blood.2009;114:4507-4516)