Driven to death: Inhibition of farnesylation increases Ras activity and promotes growth arrest and cell death [corrected].
Driven to death: Inhibition of farnesylation increases Ras activity and promotes growth arrest and cell death [corrected].
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DOI：
10.1158/1535-7163.mct-09-0833
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发表时间：
2010-05
影响因子：
5.7
通讯作者：
Hughes DP
中科院分区：
文献类型：
--
作者：
Geryk-Hall M;Yang Y;Hughes DP
为了改善癌症的结果，研究人员越来越多地转向破坏重要信号级联的小分子药物，抑制恶性肿瘤的生长或诱导细胞凋亡。一种重要的信号分子是Ras，Ras活化的关键步骤是通过异戊烯化（在C端添加脂质锚）将Ras锚定在膜上。法尼基转移酶（FTI），最常负责异戊二烯化Ras的酶的小分子抑制剂，显示出临床前景，但FTI如替吡法尼的开发已被其作用机制的不确定性所阻碍，因为Ras在替吡法尼处理的样品中似乎不受阻碍。解释进一步复杂的许多蛋白质，可能是法尼基化，以及可用性的替代异戊二烯化途径，香叶基香叶基化。骨肉瘤细胞系对替吡法尼的不同反应的初步观察使我们使用骨肉瘤模型评估FTI在Ras信号改变中的作用。我们描述了我们的新的，反直觉的发现，内源性Ras活性增加，在骨肉瘤法尼基转移酶被tipifarnib或shRNA抑制时。响应于替吡法尼，可变生长停滞和/或细胞死亡与活化ERK和p38 MAPK的水平相关。对替吡法尼治疗的敏感性表现为生长抑制和亚二倍体细胞数量的增加;具有这种敏感性的细胞增加了ERK和p38 MAPK的激活。由于Ras必须被异戊烯化才有活性，我们的研究结果表明，在对替吡法尼B反应敏感的骨肉瘤细胞中，香叶基香叶基化的N-Ras或K-Ras B与下游效应蛋白的相互作用不同，从而将细胞增殖的平衡切换到生长抑制。
To improve cancer outcomes, investigators are turning increasingly to small molecule medicines that disrupt vital signaling cascades, inhibiting malignant growth or inducing apoptosis. One vital signaling molecule is Ras, and a key step in Ras activation is membrane anchoring of Ras through prenylation, the C-terminal addition of a lipid anchor. Small molecule inhibitors of farnesyl transferase (FTI), the enzyme most often responsible for prenylating Ras, showed cinical promise, but development of FTI such as tipifarnib has been stalled by uncertainty about their mechanism of action, since Ras appeared unimpeded in tipifarnib-treated samples. Interpretation was further complicated by the numerous proteins that may be farnesylated, as well as availability of an alternate prenylation pathway, geranylgeranylation. Initial observations of varied response by osteosarcoma cell lines to tipifarnib led us to evaluate the role of FTI in Ras signal alteration using osteosarcoma models. We describe our novel, counter-intuitive finding that endogenous Ras activity increases in osteosarcoma when farnesyl transferase is inhibited either by tipifarnib or shRNA. In response to tipifarnib, variable growth arrest and/or cell death correlated with levels of activated ERK and p38 MAPK. Sensitivity to tipifarnib treatment was shown by growth inhibition and by an increase in subdiploid cell numbers; cells with such sensitivity had increased activation of ERK and p38 MAPK. Since Ras must be prenylated to be active, our findings suggest that geranylgeranylated N-Ras or K-Ras B interact differently with downstream effector proteins in sensitive osteosarcoma cells responding to tipifarnib, switching the balance from cell proliferation to growth inhibition.