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Involvement of p38 MAPK signaling pathway in cancer therapy

p38 MAPK 信号通路参与癌症治疗

基本信息

批准号：
16590569
负责人：
TANNO Satoshi
金额：
$ 2.3万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590569/
关键词：
GI cancer pancreatic cancer p38 MAPK Anticancer agents Gemcitabine chemoresistance acquired chemoresistance COX-2 p38 MAPK 細胞内シグナル伝達膵癌細胞 AKT アポトーシス

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 (Cancer Res 2004,Biochem Biophys Res Commun 2004,Anticancer Res 2005). 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.

有报道称p38 MAPK可被多种细胞外刺激激活，参与调控细胞存活和死亡的机制。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（cancer Res 2004,Biochem Biophys Res Commun 2004, anticancer Res 2005）。我们发现抑制p38 MAPK激活降低了吉西他滨诱导的细胞毒性，表明p38 MAPK激活调节了吉西他滨的敏感性。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，我们建立了多种吉西他滨耐药的人胰腺癌细胞系亚克隆，并研究了p38 MAPK的激活情况。我们发现，与亲代细胞相比，耐吉西他滨亚克隆中的p38激活降低。此外，我们发现非受体酪氨酸激酶Src被激活，并且与亲本细胞相比，p38 mapk无活性抗性亚克隆中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死亡是必要的。基于这些结果，我们建议将p38 MAPK信号通路分子列为吉西他滨治疗的新靶点。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of cell invasion and morphological change by troglitazone in human pancreatic cancer cells

DOI：
10.1007/s00535-003-1324-3
发表时间：
2004-05-01
期刊：
JOURNAL OF GASTROENTEROLOGY
影响因子：
6.3
作者：
Motomura, W;Nagamine, M;Okumura, T
通讯作者：
Okumura, T

Involvement of MEK-ERK signaling pathway in the inhibition of cell growth by troglitazone in human pancreatic cancer cells

DOI：
10.1016/j.bbrc.2005.04.095
发表时间：
2005-06-24
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Motomura, W;Tanno, S;Okumura, T
通讯作者：
Okumura, T

Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance

DOI：
10.1158/0008-5472.can-03-1788
发表时间：
2004-05-15
期刊：
CANCER RESEARCH
影响因子：
11.2
作者：
Tanno, S;Yanagawa, N;Kohgo, Y
通讯作者：
Kohgo, Y

Activation of p38 mitogen-activated protein kinase is necessary for gemcitabine-induced cytotoxicity in human pancreatic cancer cells.

DOI：
发表时间：
2005-09
期刊：
Anticancer research
影响因子：
2
作者：
K. Koizumi;S. Tanno;Y. Nakano;Atsuya Habiro;T. Izawa;Y. Mizukami;T. Okumura;Y. Kohgo
通讯作者：
K. Koizumi;S. Tanno;Y. Nakano;Atsuya Habiro;T. Izawa;Y. Mizukami;T. Okumura;Y. Kohgo

Inhibition of cell invasion and morphological change by troglitazone in cultured human pancreatic cancer cells.

曲格列酮对培养的人胰腺癌细胞的细胞侵袭和形态变化的抑制作用。