Inhibition of Epithelial-to-Mesenchymal Transition (EMT) in Cancer by Nitric Oxide: Pivotal Roles of Nitrosylation of NF-κB, YY1 and Snail.
Inhibition of Epithelial-to-Mesenchymal Transition (EMT) in Cancer by Nitric Oxide: Pivotal Roles of Nitrosylation of NF-κB, YY1 and Snail.
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DOI：
10.1615/forumimmundisther.2012006065
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Baritaki S
中科院分区：
文献类型：
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作者：
Bonavida B;Baritaki S
通过一氧化氮供体(如DETANONOate)治疗高水平一氧化氮(NO)的癌细胞株，可抑制细胞生长和生存途径，并通过化疗免疫治疗药物使耐药肿瘤细胞对凋亡敏感。此外，我们最近报道，NO还通过调节核因子-κB/Snail/阴阳1(YY1)/Raf激酶抑制蛋白通路来抑制转移性癌细胞系上皮向间充质转化的表型。研究了NO介导该环路失调的机制，即NO介导的转录因子NF-κB、Snail和YY1活性的抑制。我们推测，NO介导的抑制机制之一可能触发了NO诱导的这些转录因子的S亚硝化。我们在转移性和EMT+人前列腺癌细胞系中证明，NO处理会导致NF-κB(P50)、Snail和YY1的S亚硝化，并抑制它们的活性，导致EMT表型逆转为间充质-上皮转化表型。这些发现表明，在逆转耐药和抑制EMT和转移方面，NO供体可能是潜在的治疗剂。
Treatment of cancer cell lines with high levels of nitric oxide (NO) via NO donors, such as DETANONOate, inhibits cell growth and survival pathways and sensitizes resistant tumor cells to apoptosis by chemoimmunotherapeutic drugs. In addition, we recently have reported that NO also inhibits the epithelial-to-mesenchymal transition (EMT) phenotype in metastatic cancer cell lines via dysregulation of the nuclear factor (NF)-κB/Snail/Yin Yang 1 (YY1)/Raf kinase inhibitor protein circuitry. The mechanism underlying NO-mediated dysregulation of this circuit was investigated, namely, NO-mediated inhibition of the activity of the transcription factors NF-κB, Snail, and YY1. We hypothesized that one mechanism of NO-mediated inhibition may invoke the NO-induced S-nitrosylation of these transcription factors. We demonstrate in metastatic and EMT+ human prostate carcinoma cell lines that treatment with NO results in the S-nitrosylation of NF-κB (p50), Snail, and YY1 and inhibits their activities, resulting in the reversal of the EMT phenotype into a mesenchymal-to-epithelial transition phenotype. These findings suggest that NO donors may be potential therapeutic agents in both the reversal of resistance and the inhibition of EMT and metastasis.