Anti-androgen 2-hydroxyflutamide modulates cadherin, catenin and androgen receptor phosphorylation in androgen-sensitive LNCaP and androgen-independent PC3 prostate cancer cell lines acting via PI3K/Akt and MAPK/ERK1/2 pathways.
Anti-androgen 2-hydroxyflutamide modulates cadherin, catenin and androgen receptor phosphorylation in androgen-sensitive LNCaP and androgen-independent PC3 prostate cancer cell lines acting via PI3K/Akt and MAPK/ERK1/2 pathways.
复制标题
DOI：
10.1016/j.tiv.2017.01.019
复制
发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
E. Gorowska-Wojtowicz;A. Hejmej;A. Kamińska;L. Pardyak;M. Kotula-Balak;J. Dulińska-Litewka;P. Laidler-P.-L
中科院分区：
文献类型：
--
作者：
E. Gorowska-Wojtowicz;A. Hejmej;A. Kamińska;L. Pardyak;M. Kotula-Balak;J. Dulińska-Litewka;P. Laidler-P.-L
本研究旨在探讨抗雄激素2-羟基芴醇（HF）对前列腺癌细胞系钙粘蛋白/连环蛋白复合物和雄激素受体（AR）磷酸化的快速影响。此外，PI 3 K/Akt和MAPK/ERK 1/2途径在介导这些效应中的作用也被探索。我们已经证明，在雄激素敏感的LNCaP细胞中，HF以MAPK/ERK 1/2依赖的方式诱导E-cadherin在Ser 838/840的磷酸化快速增加（p < 0.05），而β-catenin在Tyr 654的磷酸化没有变化。同时，发现在Ser 210/213处磷酸化的AR水平降低（p < 0.01）。在雄激素非依赖性PC 3细胞中，HF通过MAPK/ERK 1/2和PI 3 K/Akt途径降低Tyr 860 N-钙粘蛋白和Tyr 645 β-连环蛋白磷酸化（p < 0.01）。此外，我们证明了MAPK/ERK 1/2和PI 3 K/Akt途径在LNCaP和PC 3细胞中受到HF的不同影响。在LNCaP细胞中，Akt（p < 0.01）和ERK 1/2（p < 0.001）磷酸化均受到负调节，并且这种作用由Raf-1介导（p < 0.05）。相反，在PC 3细胞中，HF刺激Akt（p < 0.001）和ERK 1/2（p < 0.001）活化，但在Raf-1激酶水平上对PI 3 K/Akt和MEK/ERK 1/2通路之间的串扰没有影响。我们的研究结果将抗雄激素的作用扩展到非基因组信号传导，在前列腺癌细胞中建立了抗雄激素作用和粘附连接蛋白磷酸化之间的联系。
This study aimed to investigate rapid effect of anti-androgen 2-hydroxyflutamide (HF) on cadherin/catenin complex and androgen receptor (AR) phosphorylation in prostate cancer cell lines. In addition, a role of PI3K/Akt and MAPK/ERK1/2 pathways in mediating these effects was explored. We have demonstrated that in androgen-sensitive LNCaP cells HF induced rapid increase of E-cadherin phosphorylation at Ser 838/840 (p < 0.05) in MAPK/ERK1/2-dependent manner, whereas phosphorylation of β-catenin at Tyr 654 was unchanged. Concomitantly, the reduction of the level of AR phosphorylated at Ser210/213 was found (p < 0.01). In androgen-independent PC3 cells HF decreased Tyr 860 N-cadherin and Tyr 645 β-catenin phosphorylation (p < 0.01), acting via both MAPK/ERK1/2 and PI3K/Akt pathways. Further, we evidenced that MAPK/ERK1/2 and PI3K/Akt pathways were differentially influenced by HF in LNCaP and PC3 cells. In LNCaP cells, both Akt (p < 0.01) and ERK1/2 (p < 0.001) phosphorylation were negatively regulated and this effect was mediated by Raf-1 (p < 0.05). In contrast, in PC3 cells HF stimulated Akt (p < 0.001) and ERK1/2 (p < 0.001) activation, but had no effect on the crosstalk between PI3K/Akt and MEK/ERK1/2 pathways at the Raf-1 kinase level. Our findings expand the role of anti-androgen into non-genomic signaling, creating a link between anti-androgen action and phosphorylation of adherens junction proteins in prostate cancer cells.