权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

p38 MAPK signaling pathway-induced cell death in cancer chemotherapy

p38 MAPK 信号通路诱导癌症化疗中的细胞死亡

基本信息

批准号：
18590711
负责人：
TANNO Satoshi
金额：
$ 2.53万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

It has been reported that p38 MAPK is activated by various extracellular stimuli, and involved in the mechanism of regulating cell survival and death. We have demonstrated that p38 MAPK is strongly activated by gemcitabine, an anticancer drug, and plays a significant role in gemcitabine-induced cell death in human cancer cells. We found that inhibition of p38 MAPK activation decreased the gemcitabine-induced cytotoxicity, indicating that p38 MAPK activation regulates gemcitabine sensitivity. To further investigate whether p38 MAPK is involved in the acquired chemoresistance induced by gemcitabine, we established various gemcitabine-resistant subclones of human pancreatic cancer cell lines, and investigated the activation of p38 MAPK. We found that p38 activation was decreased in the gemcitabine-resistant subclones compared with parental cells. Furthermore, we found that Src, non-receptor tyrosine kinase, was activated, and expression of COX-2 was increased in p38 MAPK-inactive resistant subclones compared with parental cells.These results suggest that activation of p38 MAPK signaling is necessary for gemcitabine-induced cell death in human pancreatic cancer cells. Based upon these results, we would suggest that molecules of p38 MAPK signaling pathways should be listed as novel targets for gemcitabine-based therapy.

有报道p38 MAPK被多种细胞外刺激激活，参与调节细胞生存和死亡的机制。我们已经证明 p38 MAPK 被抗癌药物吉西他滨强烈激活，并在吉西他滨诱导的人类癌细胞细胞死亡中发挥重要作用。我们发现抑制 p38 MAPK 激活可降低吉西他滨诱导的细胞毒性，表明 p38 MAPK 激活可调节吉西他滨敏感性。为了进一步研究p38 MAPK是否参与吉西他滨诱导的获得性化疗耐药，我们建立了各种吉西他滨耐药的人胰腺癌细胞系亚克隆，并研究了p38 MAPK的激活。我们发现与亲代细胞相比，吉西他滨耐药亚克隆中 p38 的激活有所减少。此外，我们发现与亲本细胞相比，p38 MAPK失活的耐药亚克隆中非受体酪氨酸激酶Src被激活，COX-2的表达增加。这些结果表明p38 MAPK信号的激活对于吉西他滨诱导的人胰腺癌细胞细胞死亡是必要的。基于这些结果，我们建议 p38 MAPK 信号通路分子应列为基于吉西他滨的治疗的新靶点。