Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells.
Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells.
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DOI：
10.1038/bjc.2012.582
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发表时间：
2013-02-05
影响因子：
8.8
通讯作者：
Richardson, D. R.
中科院分区：
文献类型：
--
作者：
Dixon, K. M.;Lui, G. Y. L.;Kovacevic, Z.;Zhang, D.;Yao, M.;Chen, Z.;Dong, Q.;Assinder, S. J.;Richardson, D. R.
前列腺癌的有效治疗应该基于肿瘤细胞信号传导通路和关键会聚下游效应物之间的靶向相互作用。在此，我们确定了致瘤性磷酸肌醇3-激酶/蛋白激酶B（PI 3 K/AKT）、10号染色体上缺失的肿瘤抑制性磷酸酶和张力蛋白同源物（PTEN）以及转化生长因子-β（TGF-β）途径如何通过转移抑制因子N-myc下游调节基因-1（NDRG 1）整合。此外，我们评估了新型抗肿瘤药物Dp 44 mT如何通过增加NDRG 1表达来靶向这些整合途径。通过蛋白质印迹法评估Dp 44 mT处理的正常人前列腺上皮细胞和前列腺癌细胞（PC-3，DU 145）中的蛋白质表达。通过使用NDRG 1过表达载体或shRNA转染来检查NDRG 1的作用。Dp 44 mT增加了肿瘤抑制性PTEN的水平，并降低了ERK 1/2和SMAD 2L的磷酸化，这是由致癌Ras/MAPK信号转导调节的。重要的是，Dp 44 mT对NDRG 1和p-SMAD 2L表达的影响在前列腺癌细胞中比正常前列腺上皮细胞更显著。这可能部分解释了这些药物的抗肿瘤选择性。NDRG 1表达沉默增加了致瘤AKT、ERK 1/2和SMAD 2L的磷酸化，降低了PTEN水平，而NDRG 1过表达诱导了相反的效果。此外，NDRG 1沉默显著降低了Dp 44 mT抑制p-SMAD 2L和p-ERK 1/2水平的能力。NDRG 1通过选择性靶向PI 3 K/AKT、TGF-β和ERK通路，在介导Dp 44 mT在前列腺癌中的肿瘤抑制作用中具有重要作用。
Effective treatment of prostate cancer should be based on targeting interactions between tumour cell signalling pathways and key converging downstream effectors. Here, we determined how the tumourigenic phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), tumour-suppressive phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and transforming growth factor-β (TGF-β) pathways are integrated via the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1). Moreover, we assessed how the novel anti-tumour agent, Dp44mT, may target these integrated pathways by increasing NDRG1 expression. Protein expression in Dp44mT-treated normal human prostate epithelial cells and prostate cancer cells (PC-3, DU145) was assessed by western blotting. The role of NDRG1 was examined by transfection using an NDRG1 overexpression vector or shRNA. Dp44mT increased levels of tumour-suppressive PTEN, and decreased phosphorylation of ERK1/2 and SMAD2L, which are regulated by oncogenic Ras/MAPK signalling. Importantly, the effects of Dp44mT on NDRG1 and p-SMAD2L expression were more marked in prostate cancer cells than normal prostate epithelial cells. This may partly explain the anti-tumour selectivity of these agents. Silencing NDRG1 expression increased phosphorylation of tumourigenic AKT, ERK1/2 and SMAD2L and decreased PTEN levels, whereas NDRG1 overexpression induced the opposite effect. Furthermore, NDRG1 silencing significantly reduced the ability of Dp44mT to suppress p-SMAD2L and p-ERK1/2 levels. NDRG1 has an important role in mediating the tumour-suppressive effects of Dp44mT in prostate cancer via selective targeting of the PI3K/AKT, TGF-β and ERK pathways.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
3.6
作者：
Kovacevic, Zaklina;Chikhani, Sherin;Richardson, Des R.
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影响因子：
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作者：
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del Peso, L
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作者：
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2.3
作者：
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