Selective potentiation of paclitaxel (Taxol)-induced cell death by mitogen-activated protein kinase kinase inhibition in human cancer cell lines
Selective potentiation of paclitaxel (Taxol)-induced cell death by mitogen-activated protein kinase kinase inhibition in human cancer cell lines
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DOI：
10.1124/mol.60.2.290
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发表时间：
2001-08-01
影响因子：
3.6
通讯作者：
Horwitz, SB
中科院分区：
文献类型：
--
作者：
McDaid, HM;Horwitz, SB
研究了用紫杉醇（Taxol）和其他微管相互作用剂处理后HeLa和中国仓鼠卵巢细胞中丝裂原活化蛋白激酶（MAPK）途径的激活。使用trans-reporting系统，测量核转录因子Elk-1和c-jun的磷酸化。观察到主要由MAPK家族的细胞外信号调节激酶（ERK）组分介导的Elk-1途径的浓度和时间依赖性激活。不靶向微管的非活性药物类似物和其他细胞毒性化合物未能诱导类似水平的活化，从而表明这些药物与微管之间的相互作用对于MAPK的活化是必不可少的。MAPK表达的内源性水平的评价揭示了ERK，c-jun N-末端激酶和p38途径的细胞依赖性表达。在HeLa细胞的情况下，ERK的时间依赖性激活与增加的聚（ADP-核糖）聚合酶（PARP）裂解，磷脂酰丝氨酸外化，并增加细胞在GA中的积累相一致。在这两种细胞系中，ERK活性的抑制增强紫杉醇的PARP裂解和磷脂酰丝氨酸外化，这表明ERK活性与紫杉醇的细胞毒性作用相一致，但不介导紫杉醇的细胞毒性作用。我们评估了紫杉醇和MAPK激酶抑制剂U 0126在三种细胞系中相互作用的性质，基于紫杉醇加ERK抑制的潜在化疗优势。我们的数据证实了在那些经历紫杉醇诱导的ERK激活的细胞系中的加和性，以及在具有低ERK活性的细胞中的拮抗性，这表明在具有高ERK活性的肿瘤中，这种策略可能在治疗中有应用。
Activation of the mitogen-activated protein kinase (MAPK) pathway in HeLa and Chinese hamster ovary cells after treatment with paclitaxel (Taxol) and other microtubule interacting agents has been investigated. Using a trans-reporting system, the phosphorylation of the nuclear transcription factors Elk-1 and c-jun was measured. Concentration- and time-dependent activation of the Elk-1 pathway, mediated primarily by the extracellular signal-regulated kinase (ERK) component of the MAPK family, was observed. Inactive drug analogs and other cytotoxic compounds that do not target microtubules failed to induce similar levels of activation, thereby indicating that an interaction between these drugs and the microtubule is essential for the activation of MAPKs. Evaluation of the endogenous levels of MAPK expression revealed cell-dependent expression of the ERK, c-jun N-terminal kinase, and p38 pathways. In the case of HeLa cells, time-dependent activation of ERK coincided with increased poly(ADP-ribose) polymerase (PARP) cleavage, phosphatidylserine externalization, and increased accumulation of cells in GA In both cell lines, inhibition of ERK activity potentiated paclitaxel-incluced PARP cleavage and phosphatidylserine externalization, suggesting that ERK activity coincided with, but did not mediate, the cytotoxic effects of paclitaxel. We evaluated the nature of the interaction between paclitaxel and the MAPK kinase inhibitor U0126 in three cell lines, on the basis of a potential chemotherapeutic advantage of paclitaxel plus ERK inhibition. Our data confirmed additivity in those cells lines that undergo paclitaxel-induced ERK activation, and antagonism in cells with low ERK activity, suggesting that in tumors with high ERK activity, there may be an application for this strategy in therapy.