Mechanisms of nitric oxide-mediated inhibition of EMT in cancer Inhibition of the metastasis-inducer snail and induction of the metastasis-suppressor RKIP
Mechanisms of nitric oxide-mediated inhibition of EMT in cancer Inhibition of the metastasis-inducer snail and induction of the metastasis-suppressor RKIP
复制标题
DOI：
10.4161/cc.9.24.14229
复制
发表时间：
2010-12-15
期刊：
影响因子：
4.3
通讯作者：
Bonavida, Benjamin
中科院分区：
文献类型：
--
作者：
Baritaki, Stavroula;Huerta-Yepez, Sara;Bonavida, Benjamin
一氧化氮（NO）在癌症中的作用一直存在争议，并且基于NO水平和肿瘤类型的反应性。NO是否能抑制癌细胞的上皮间质转化（EMT）尚不清楚。EMT的诱导部分是由转移诱导转录因子的组成性激活介导的，Snail和EMT可以被转移抑制因子Raf-1激酶抑制蛋白（RKIP）和E-cadherin抑制。Snail受NF κ B B转录调控，反过来，Snail抑制RKIP转录。因此，我们假设高水平的NO抑制NF κ B活性，也可能抑制Snail并诱导RKIP，从而抑制EMT。我们发现，用NO供体DETANONOate处理人前列腺转移细胞系，抑制EMT并逆转间充质表型和细胞侵袭特性。此外，用DETANONOate处理抑制Snail表达和DNA结合活性，同时上调RKIP和E-钙粘蛋白蛋白水平。Snail抑制和RKIP诱导在DETANONOATE介导的EMT抑制中的关键作用通过siRNA的Snail沉默和RKIP的异位表达得到证实。在携带PC-3异种移植物并接受DETANONOate治疗的小鼠中，体内验证了体外结果。目前的研究结果表明，第一次，高亚毒性浓度的NO在抑制EMT的新作用。因此，NO供体可能在逆转EMT和转移中发挥治疗活性。
The role of nitric oxide (NO) in cancer has been controversial and is based on the levels of NO and the responsiveness of the tumor type. It remains unclear whether NO can inhibit the epithelial to mesenchymal transition (EMT) in cancer cells. EMT induction is mediated, in part, by the constitutive activation of the metastasis-inducer transcription factor, Snail and EMT can be inhibited by the metastasis-suppressor Raf-1 kinase inhibitor protein (RKIP) and E-cadherin. Snail is transcriptionally regulated by NF kappa B and in turn, Snail represses RKIP transcription. Hence, we hypothesized that high levels of NO, that inhibit NF kappa B activity, may also inhibit Snail and induce RKIP and leading to inhibition of EMT. We show that treatment of human prostate metastatic cell lines with the NO donor, DETANONOate, inhibits EMT and reverses both the mesenchymal phenotype and the cell invasive properties. Further, treatment with DETANONOate inhibits Snail expression and DNA-binding activity in parallel with the upregulation of RKIP and E-cadherin protein levels. The pivotal roles of Snail inhibition and RKIP induction in DETANONOate-mediated inhibition of EMT were corroborated by both Snail silencing by siRNA and by ectopic expression of RKIP. The in vitro findings were validated in vivo in mice bearing PC-3 xenografts and treated with DETANONOate. The present findings show, for the first time, the novel role of high subtoxic concentrations of NO in the inhibition of EMT. Thus, NO donors may exert therapeutic activities in the reversal of EMT and metastasis.