Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells
Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells
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DOI：
10.1002/pros.20117
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发表时间：
2005-01-01
期刊：
影响因子：
2.8
通讯作者：
Murai, M
中科院分区：
文献类型：
--
作者：
Ohigashi, T;Mizuno, R;Murai, M
背景前列腺癌（Pca）中Wnt信号传导和Akt通路之间的相互作用尚不清楚。在本研究中，我们发现WIF-1下调Akt通路，并增强PTEN缺失的Pca细胞的化疗敏感性。将Wnt抑制因子-1（WIF-1）转染PC-3和DU 145 Pca细胞，观察Wnt抑制因子-1（WIF-1）对PC-3和DU 145 Pca细胞增殖的影响。Akt在PTEN缺失的PC-3细胞中磷酸化，但在表达PTEN的DU 145细胞中磷酸化不足。过表达WIF-1的PC-3细胞中磷酸化Akt的水平低于天然或对照载体转染的PC-3细胞。然而，WIF-1在DU 145细胞中没有显示出对已经降低的Akt活性的额外抑制。过表达WIF-1可使PC-3细胞对紫杉醇敏感，诱导细胞凋亡。DU 145细胞对紫杉醇更敏感，但不受WIF-1转染的影响。P13 K抑制剂LY 294002与WTF-1一样，可恢复PC-3细胞对化疗药物的敏感性。我们的研究结果表明，Wnt信号参与Pca细胞中Akt的激活。我们的数据还表明Wnt及其信号通路可能是PTEN突变的晚期Pca的治疗靶点。(C)2004 Wiley-Liss，Inc.
BACKGROUND. The cross-talk between Wnt signaling and the Akt pathway in prostate cancer (Pca) is still unclear. In the present study, we found that WIF-1 downregulates the Akt pathway and also enhances chemosensitivity in PTEN-null Pca cells.METHODS. Wnt inhibitory factor-1 (WIF-1), an inhibitor of Wnt proteins, was transfected into PC-3 and DU145 Pca cells.RESULTS. Akt was phosphorylated in PTEN-null PC-3 cells but underphosphorylated in PTEN-expressed DU145 cells. The levels of phosphorylated Akt in WIF-1 overexpressing PC-3 cells were lower than those in native or control vector-transfected PC-3 cells. However, WIF-1 showed no additional inhibition of already reduced Akt activity in DU145 cells. Overexpression of WIF-1 resulted in sensitizing PC-3 cells for paclitaxel to induce apoptosis. DU145 cells were more sensitive to paclitaxel but were not affected by WIF-1 transfection. The P13K inhibitor LY294002 seemed to restore the chemosensitivity of native PC-3 cells like WTF-1 did.CONCLUSIONS. Our results show that Wnt signaling is involved in Akt activation in Pca cells. Our data also indicate the possibility that Wnt and its signaling pathway can be therapeutic targets for PTEN-mutated advanced Pca. (C) 2004 Wiley-Liss, Inc.