LEDGF gene silencing impairs the tumorigenicity of prostate cancer DU145 cells by abating the expression of Hsp27 and activation of the Akt/ERK signaling pathway.
LEDGF gene silencing impairs the tumorigenicity of prostate cancer DU145 cells by abating the expression of Hsp27 and activation of the Akt/ERK signaling pathway.
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DOI：
10.1038/cddis.2012.57
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发表时间：
2012-05-31
影响因子：
9
通讯作者：
Singh DP
中科院分区：
文献类型：
--
作者：
Bhargavan B;Fatma N;Chhunchha B;Singh V;Kubo E;Singh DP
晶状体上皮衍生生长因子（LEDGF）通过增加应激反应基因（如小热休克蛋白27）的转录来维持存活途径。近年来，在前列腺癌（PC）中发现了LEDGF的异常表达。本研究表明，LEDGF过表达上调PC细胞中的Hsp27、DU145、PC-3和LNCaP，促进PC细胞的抗凋亡通路。我们发现这些细胞具有更高的Hsp27丰度，这与LEDGF表达水平相关。DU145细胞的反活化实验显示，Hsp27的反活化与LEDGF的表达量有关。在DU145细胞中，沉默LEDGF可抑制Hsp27的表达，抑制受刺激的细胞增殖、侵袭性和迁移。这些细胞停留在S期和G2期，细胞周期蛋白B1无法积累，细胞凋亡增加。此外，ledgf缺失的DU145细胞显示Bax和cleaved caspase 9表达升高，Bcl2、Bcl-XL水平降低。活化的存活通路ERK1/2和Akt在这些细胞中选择性降低，其特点是具有较低的致瘤性。相反，当LEDGF或Hsp27再次过表达时，耗尽的细胞恢复了致瘤特性。总的来说，结果揭示了ledgf介导的hsp27依赖性生存途径的表达升高参与了PC。我们的发现提示了新的研究路线，旨在开发针对LEDGF或其异常表达相关的刺激抗凋亡途径的治疗方法。
Lens epithelium-derived growth factor (LEDGF) maintains survival pathways by augmenting the transcription of stress-response genes such as small heat-shock protein 27. Recently, aberrant expression of LEDGF was found in prostate cancer (PC). Herein, we showed that LEDGF overexpression upregulated Hsp27 in PC cells, DU145, PC-3 and LNCaP and promoted antiapoptotic pathways in PCs. We found that these cells had higher abundance of Hsp27, which was correlated with the levels of LEDGF expression. Transactivation assay in DU145 cells revealed that transactivation of Hsp27 was related to the magnitude of LEDGF expression. Silencing of LEDGF in DU145 cells abrogated Hsp27 expression and inhibited stimulated cell proliferation, invasiveness and migration. These cells were arrested in S and G2 phase, and failed to accumulate cyclin B1, and showed increased apoptosis. Furthermore, LEDGF-depleted DU145 cells displayed elevated Bax and cleaved caspase 9 expression and reduced levels of Bcl2, Bcl-XL. The activated survival pathway(s), ERK1/2 and Akt, were selectively decreased in these cells, which characteristically have lower tumorigenicity. Conversely, the depleted cells, when re-overexpressed with LEDGF or Hsp27, regained tumorigenic properties. Collectively, results reveal the involvement of LEDGF-mediated elevated expression of Hsp27-dependent survival pathway(s) in PC. Our findings suggest new lines of investigation aimed at developing therapies by targeting LEDGF or its aberrant expression-associated stimulated antiapoptotic pathway(s).
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影响因子：
4.8
作者：
Mehlen, P;SchulzeOsthoff, K;Arrigo, AP
通讯作者：
Arrigo, AP
DOI：
10.1006/bbrc.2000.3606
发表时间：
2000-10-05
影响因子：
3.1
作者：
Sharma, P;Singh, DP;Shinohara, T
通讯作者：
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影响因子：
3.8
作者：
Long, Xiang-E;Gong, Zhao-Hui;Zhong, Jiu-Chang
通讯作者：
Zhong, Jiu-Chang
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影响因子：
37.3
作者：
Huang, Tien-sheng;Myklebust, Line M;Kjarland, Endre;Gjertsen, Bjorn Tore;Pendino, Frederic;Bruserud, Oystein;Doskeland, Stein Ove;Lillehaug, Johan R
通讯作者：
Lillehaug, Johan R
影响因子：
11.4
作者：
Ge, H;Si, YZ;Roeder, RG
通讯作者：
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