Bonavida Benjamin, Baritaki Stavroula
Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California.
For Immunopathol Dis Therap. 2012;3(2):125-133. doi: 10.1615/ForumImmunDisTher.2012006065.
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.
通过一氧化氮（NO）供体（如二乙三胺 NONO 酸盐）对癌细胞系进行高水平的 NO 处理，可抑制细胞生长和存活途径，并使耐药肿瘤细胞对化学免疫治疗药物诱导的凋亡敏感。此外，我们最近报道，NO 还通过核因子（NF）-κB/蜗牛蛋白（Snail）/阴阳 1（YY1）/Raf 激酶抑制蛋白信号通路失调，抑制转移性癌细胞系中的上皮-间质转化（EMT）表型。研究了 NO 介导该信号通路失调的机制，即 NO 介导对转录因子 NF-κB、Snail 和 YY1 活性的抑制。我们假设 NO 介导抑制的一种机制可能是 NO 诱导这些转录因子的 S-亚硝基化。我们在转移性和发生 EMT 的人前列腺癌细胞系中证明，用 NO 处理会导致 NF-κB（p50）、Snail 和 YY1 的 S-亚硝基化，并抑制它们的活性，从而使 EMT 表型逆转为间质-上皮转化表型。这些发现表明，NO 供体可能是逆转耐药性以及抑制 EMT 和转移的潜在治疗药物。
