Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells
Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells
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DOI：
10.1002/pros.10292
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发表时间：
2004-01-01
期刊：
影响因子：
2.8
通讯作者：
Lazo, JS
中科院分区：
文献类型：
--
作者：
Nemoto, K;Vogt, A;Lazo, JS
背景丝氨酸/苏氨酸激酶Raf-1是丝裂原活化蛋白激酶（MAPK）途径的主要调节剂，其与前列腺癌向更晚期和雄激素非依赖性疾病的进展相关。Cdc 25 A磷酸酶参与Raf-1和MAPK通路的调节。我们使用一种新的和有效的Cdc 25 A抑制剂，2，3-双-[2-羟乙基磺酰基][1，4]萘醌（NSC 95397），及其同系物（2-巯基乙醇）-3-甲基-1，4-萘醌（NSC 672121）来研究Cdc 25 A在人前列腺癌细胞中MAPK通路中的作用。我们发现Raf-1在PC-3和LNCap细胞中与Cdc 25 A发生物理相互作用，Cdc 25 A的抑制剂诱导细胞外信号调节激酶（Erk）激活和Raf-1酪氨酸磷酸化。NSC 95397减弱Cdc 25 A和Raf-1的相互作用，由于Cdc 25 A的加速降解，这是由蛋白酶体降解介导的。MAPK激酶（MEK）抑制剂U 0126可完全抑制NSC 95397和NSC 672121对Erk的激活。这些结果表明Cdc 25 A磷酸酶调节人前列腺癌细胞Raf-1/MEK/Erk激酶活化。(C)2004 Wiley-Liss，Inc.
BACKGROUND. The serine/threonine kinase Raf-1 is a major regulator of the mitogen activated protein kinase (MAPK) pathway, which has been associated with the progression of prostate cancer to the more advanced and androgen-independent disease. Cdc25A phosphatase has been implicated in the regulation of Raf-1 and the MAPK pathway.METHODS. We used a novel and potent Cdc25A inhibitor, 2,3-bis-[2-hydroxyethylsulfonyll[1,4] naphthoquinone (NSC 95397), and its congener (2-mercaptoethanol)-3-methyl-1, 4-naphthoquinone (NSC 672121) to study the role of Cdc25A on the MAPK pathway in human prostate cancer cells.RESULTS. We found Raf-1 physically interacted with Cdc25A in PC-3 and LNCap cells and inhibitors of Cdc25A induced both extracellular signal-regulated kinase (Erk) activation and Raf-1 tyrosine phosphorylation. NSC 95397 attenuated Cdc25A and Raf-1 interactions due to accelerated degradation of Cdc25A, which was mediated by proteasome degradation. The MAPK kinase (MEK) inhibitor U0126 completely inhibited Erk activation by NSC 95397 and NSC 672121.CONCLUSIONS. These results indicate Cdc25A phosphatase regulates Raf-1/MEK/Erk kinase activation inhuman prostate cancer cells. (C) 2004 Wiley-Liss, Inc.