Basic research on novel therapy for hormone-refractory prostate cancer with tyrosine kinase

酪氨酸激酶治疗激素难治性前列腺癌的基础研究

基本信息

批准号：
13671654
负责人：
MATSUBARA Akio
金额：
$ 2.24万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671654/
关键词：
fibroblast growth factor fibroblast growth factor receptor tyrosine kinase growth inhibition differentiation prostate cancer gene therapy FGFR2IIIb ヒト前立腺癌ラクトフェリンサイトケラチン

项目摘要

We induced, by transfection, fibroblast growth factor receptor 2 Illb (FGFR2IIIb) kinase in hormone-independent human prostate cancer cell line, PC-3 cells. Consequently, the transfected PC-3 cells fell in a state of strong apoptosis and showed significantly reduced population growth rates in vitro and in vivo. In addition, the growth suppression was significantly accelerated by the addition of specific *igand for FGFR2IIIb, FGF-7. The expression levels of cytokeratin and lactoferrin, which are indicators for cell differentiation, markedly increased in the transfected PC-3 cells. These results indicate that the FGFR2IIIb has not only a growth suppressing but also differentiation inducing properties for hormone-independent prostate cancer cells.In the present study, The FGFR2IIIb signaling pathway was also analyzed by Western blotting. As a result, the FRS2 signal intensity of transfected PC-3 cells was much stronger than that of control cells. After stimulation with FGF-7, FRS2 was strongly activated in transfected PC-3, but not control, cells. Also, after stimulation with FGF-1 and FGF-7, phosphorylation of p44/42 MAP kinase was detected in transfected PC-3, but not control, cells. These results indicate that the FGFR2IIIb signals in transfected PC-3 cells are closely associated with phosphorylation of FRS2 and MAP kinase. Thus the growth suppressing and differentiation inducing properties of FGFR2IIIb were considered to be induced by the activation of FRS2 and MAP kinase.

我们通过转染，在激素非依赖性人前列腺癌细胞系PC-3细胞中诱导成纤维细胞生长因子受体2 IIIb (FGFR2IIIb)激酶。因此，转染的PC-3细胞处于强烈凋亡状态，并且在体外和体内表现出显着降低的群体增长率。此外，通过添加 FGFR2IIIb、FGF-7 的特异性*配体，生长抑制显着加速。转染的PC-3细胞中作为细胞分化指标的细胞角蛋白和乳铁蛋白的表达水平显着增加。这些结果表明，FGFR2IIIb不仅具有激素非依赖性前列腺癌细胞的生长抑制作用，而且具有诱导分化的特性。在本研究中，还通过蛋白质印迹分析了FGFR2IIIb信号通路。结果，转染的PC-3细胞的FRS2信号强度比对照细胞强得多。用 FGF-7 刺激后，转染的 PC-3 细胞中的 FRS2 被强烈激活，但对照细胞则没有。此外，用 FGF-1 和 FGF-7 刺激后，在转染的 PC-3 细胞（而非对照细胞）中检测到 p44/42 MAP 激酶的磷酸化。这些结果表明转染的PC-3细胞中的FGFR2IIIb信号与FRS2和MAP激酶的磷酸化密切相关。因此，FGFR2IIIb 的生长抑制和分化诱导特性被认为是由 FRS2 和 MAP 激酶的激活诱导的。