Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis
Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis
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DOI：
10.1158/0008-5472.can-04-0866
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Penn, LZ
中科院分区：
文献类型：
--
作者：
Wu, JH;Wong, WWL;Penn, LZ
他汀类药物家族是公认的3-羟3-甲基戊二酰辅酶a还原酶抑制剂，在临床上用于控制高胆固醇血症。我们和其他人最近的证据表明，他汀类药物也可以通过阻断蛋白质香叶酰化来引发肿瘤特异性凋亡。我们和其他人提出，他汀类药物破坏了香叶酰香叶酰化蛋白的定位和功能，这些蛋白负责激活对转化细胞生长和/或存活至关重要的信号转导途径。为了进一步探讨这一点，我们研究了丝裂原活化蛋白激酶（MAPK）信号级联是否在调节他汀类药物诱导的细胞凋亡中发挥作用。来源于急性髓性白血病（AML）的细胞被用作我们的模型系统。我们发现p38和c-Jun nh2末端激酶/应激激活激酶MAPK通路在洛伐他汀诱导的细胞凋亡过程中没有改变。相比之下，原代和已建立的AML细胞暴露于他汀类药物会导致基础细胞外信号调节激酶（ERK） 1/2磷酸化的显著破坏。添加香叶基PPi可逆转他汀类药物诱导的ERK1/2磷酸化缺失和细胞凋亡。通过在AML细胞中建立和评估可诱导的Raf-1:ER系统，我们发现Raf/MAPK激酶(MEK)/ERK通路的组成性激活显著抑制但不能完全阻断洛伐他汀诱导的细胞凋亡。我们的研究结果强烈提示他汀类药物通过调节包括Raf/MEK/ERK通路在内的多种信号通路触发细胞凋亡。事实上，Raf/MEK/ERK通路的下调增强了他汀类药物诱导的细胞凋亡，因为暴露于MEK1抑制剂PD98059使AML细胞对低的、生理上可达到的洛伐他汀浓度敏感。我们的研究表明，洛伐他汀单独或联合MEK1抑制剂可能代表一种新的、立即可用的治疗方法，用于对抗具有活化ERK1/2的肿瘤，如AML。
The statin family of drugs are well-established inhibitors of 3-hydroxy3-methylglutaryl-CoA reductase and are used clinically in the control of hypercholesterolemia. Recent evidence, from ourselves and others, shows that statins can also trigger tumor-specific apoptosis by blocking protein geranylgeranylation. We and others have proposed that statins disrupt localization and function of geranylgeranylated proteins responsible for activating signal transduction pathways essential for the growth and/or survival of transformed cells. To explore this further, we have investigated whether the mitogen-activated protein kinase (MAPK) signaling cascades play a role in regulating statin-induced apoptosis. Cells derived from acute myelogenous leukemia (AML) are used as our model system. We show that p38 and c-Jun NH2-terminal kinase/stress-activated kinase MAPK pathways are not altered during lovastatin-induced apoptosis. By contrast, exposure of primary and established AML cells to statins results in significant disruption of basal extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Addition of geranylgeranyl PPi reverses statin-induced loss of ERK1/2 phosphorylation and apoptosis. By establishing and evaluating the inducible Raf-1:ER system in AML cells, we show that constitutive activation of the Raf/MAPK kinase (MEK)/ERK pathway significantly represses but does not completely block lovastatin-induced apoptosis. Our results strongly suggest statins trigger apoptosis by regulating several signaling pathways, including the Raf/MEK/ERK pathway. Indeed, down-regulation of the Raf/MEK/ERK pathway potentiates statin-induced apoptosis because exposure to the MEK1 inhibitor PD98059 sensitizes AML cells to low, physiologically achievable concentrations of lovastatin. Our study suggests that lovastatin, alone or in combination with a MEK1 inhibitor, may represent a new and immediately available therapeutic approach to combat tumors with activated ERK1/2, such as AML.