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

我们通过转染在非依赖于凋亡的人前列腺癌细胞系PC-3细胞中诱导成纤维细胞生长因子受体2 IIIb（FGFR 2 IIIb）激酶。因此，转染的PC-3细胞处于强凋亡状态，并在体外和体内显示出显著降低的群体生长率。此外，通过添加FGFR 2 IIIb、FGF-7的特异性配体，生长抑制显著加速。细胞角蛋白和乳铁蛋白的表达水平，这是细胞分化的指标，在转染的PC-3细胞中显着增加。这些结果表明，FGFR 2 IIIb对非依赖性前列腺癌细胞不仅具有生长抑制作用，而且具有诱导分化作用。结果表明，转染PC-3细胞的FRS 2信号强度比对照细胞强得多。在用FGF-7刺激后，FRS 2在转染的PC-3细胞中被强烈激活，但在对照细胞中没有。此外，在用FGF-1和FGF-7刺激后，在转染的PC-3细胞中检测到p44/42 MAP激酶的磷酸化，但在对照细胞中未检测到。这些结果表明，转染PC-3细胞中的FGFR 2 IIIb信号与FRS 2和MAP激酶的磷酸化密切相关。因此，认为FGFR 2 IIIb的生长抑制和分化诱导性质是由FRS 2和MAP激酶的活化诱导的。

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.