Activation of p38 mitogen-activated protein kinase is necessary for gemcitabine-induced cytotoxicity in human pancreatic cancer cells.
Activation of p38 mitogen-activated protein kinase is necessary for gemcitabine-induced cytotoxicity in human pancreatic cancer cells.
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发表时间：
2005-09
影响因子：
2
通讯作者：
K. Koizumi;S. Tanno;Y. Nakano;Atsuya Habiro;T. Izawa;Y. Mizukami;T. Okumura;Y. Kohgo
中科院分区：
文献类型：
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作者：
K. Koizumi;S. Tanno;Y. Nakano;Atsuya Habiro;T. Izawa;Y. Mizukami;T. Okumura;Y. Kohgo
吉西他滨是一种嘧啶核苷类似物，临床上对胰腺癌有活性。我们最近已经证明，p38 MAPK被吉西他滨特异性激活，并且药理学阻断p38 MAPK信号传导阻止了吉西他滨诱导的人胰腺癌细胞凋亡。在这项研究中，我们进一步研究了p38 MAPK在吉西他滨细胞毒性作用中的意义。材料和方法产生表达p38 MAPK显性负突变体的细胞。克隆形成测定用于评估对人胰腺癌细胞PK1和PCI 43中癌细胞活力的长期影响。使用对磷酸化形式特异的抗体评估p38 MAPK活化水平。结果吉西他滨可剂量依赖性地增加p38 MAPK的激活水平，诱导胰腺癌细胞凋亡。选择性p38 MAPK抑制剂SB203580和SB202190可降低吉西他滨诱导的p38 MAPK激活，阻止吉西他滨诱导的细胞凋亡，并增加长期克隆形成存活。细胞中显性负性p38突变体的过表达导致吉西他滨诱导的p38 MAPK活化和凋亡减少，克隆形成存活增加。结论p38 MAPK信号通路的激活是吉西他滨诱导胰腺癌细胞死亡的必要条件。基于这些结果，我们建议p38 MAPK信号通路的分子应被列为新的吉西他滨为基础的治疗目标。
BACKGROUND Gemcitabine is a pyrimidine nucleoside analog that is clinically active against pancreatic cancer. We have recently demonstrated that p38 MAPK is specifically activated by gemcitabine and that pharmacological blockade of p38 MAPK signaling prevented gemcitabine-induced apoptosis in human pancreatic cancer cells. In this study, we further investigated the implication of p38 MAPK in the cytotoxic action of gemcitabine. MATERIALS AND METHODS Cells expressing a dominant-negative mutant of p38 MAPK were generated. Clonogenic assays were used to assess the long-term effect on cancer cell viability in the human pancreatic cancer cells, PK1 and PCI43. The p38 MAPK activation level was assessed using an antibody specific to the phosphorylated form. RESULTS Gemcitabine increased the activation level of p38 MAPK in a dose-dependent manner and induced apoptosis in the two tested human pancreatic cancer cell lines. The selective p38 MAPK inhibitors, SB203580 and SB202190, reduced gemcitabine-induced activation of p38 MAPK, prevented the gemcitabine-induced apoptosis and increased long-term clonogenic survival. Overexpression of a dominant-negative p38 mutant in cells resulted in the reduction of gemcitabine-induced p38 MAPK activation and apoptosis, and increases in clonogenic survival. CONCLUSION These results strongly suggest that the activation of p38 MAPK signaling is necessary for gemcitabine-induced cell death in human pancreatic cancer cells. Based upon these results, we suggest that molecules of p38 MAPK signaling pathways should be listed as novel targets for gemcitabine-based therapy.