Nodal pathway activation due to Akt1 suppression is a molecular switch for prostate cancer cell epithelial-to-mesenchymal transition and metastasis
Nodal pathway activation due to Akt1 suppression is a molecular switch for prostate cancer cell epithelial-to-mesenchymal transition and metastasis
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DOI：
10.1016/j.bcp.2019.06.010
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发表时间：
2019-10-01
影响因子：
5.8
通讯作者：
Somanath, Payaningal R.
中科院分区：
文献类型：
--
作者：
Alwhaibi, Abdulrahman;Verma, Arti;Somanath, Payaningal R.
一些研究已经揭示了Akt1在晚期癌症中的负面作用，包括转移性前列腺癌(MPCA)。因此，了解在MPCA中靶向Akt1的后果并确定其下游的新靶点是至关重要的。我们研究了PC3和DU145细胞中Akt1缺失如何激活Nodal通路，促进PCa上皮向间充质转化(EMT)和转移。在这里，我们发现Akt1缺失增加了Pca细胞中Nodal的表达，伴随着FoxO1/3a、EMT标志物Snail和N-cadherin的激活，以及上皮标志物E-cadherin的缺失。FoxO抑制剂AS1842856可抑制Akt1缺失的PCa细胞中Nodal的表达。AKT1基因缺陷的PCa细胞在体外表现出增强的细胞迁移和侵袭能力，并在体内表现出肺转移，这些作用可被Nodal途径抑制剂SB505124抑制。有趣的是，来自cBioPortal的两项基因组研究的Nodal mRNA分析显示，Nodal的表达与Gleason评分呈正相关，表明Nodal在人类MPCA中起着积极的作用。综上所述，我们的数据显示Akt1-FOXO3a-Nodal通路是PCa转移的重要介质，并使Nodal成为治疗MPCa患者的潜在靶点。
Several studies have unraveled the negative role of Akt1 in advanced cancers, including metastatic prostate cancer (mPCa). Hence, understanding the consequences of targeting Akt1 in the mPCa and identifying its downstream novel targets is essential. We studied how Akt1 deletion in PC3 and DU145 cells activates the Nodal pathway and promotes PCa epithelial-to-mesenchymal transition (EMT) and metastasis. Here we show that Akt1 loss increases Nodal expression in PCa cells accompanied by activation of FoxO1/3a, and EMT markers Snail and N-cadherin as well as loss of epithelial marker E-cadherin. Treatment with FoxO inhibitor AS1842856 abrogated the Nodal expression in Akt1 deleted PCa cells. Akt1 deficient PCa cells exhibited enhanced cell migration and invasion in vitro and lung metastasis in vivo, which were attenuated by treatment with Nodal pathway inhibitor SB505124. Interestingly, Nodal mRNA analysis from two genomic studies in cBioportal showed a positive correlation between Nodal expression and Gleason score indicating the positive role of Nodal in human mPCa. Collectively, our data demonstrate Akt1-FoxO3a-Nodal pathway as an important mediator of PCa metastasis and present Nodal as a potential target to treat mPCa patients.