Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
Nitric Oxide. 2011 Jan 1;24(1):1-7. doi: 10.1016/j.niox.2010.10.001. Epub 2010 Oct 8.
Several studies have implicated the role of Nitric Oxide (NO) in the regulation of tumor cell behavior and have shown that NO either promotes or inhibits tumorigenesis. These conflicting findings have been resolved, in part, by the levels of NO used such that low levels promote tumor growth and high levels inhibit tumor growth. Our studies have focused on the use of high levels of NO provided primarily by the NO donor, DETANONOate. We have shown that treatment of resistant tumor cells with DETANONOate sensitizes them to apoptosis by both chemotherapeutic drugs and cytotoxic immunotherapeutic ligands. The underlying mechanisms by which NO sensitizes tumor cells to apoptosis were shown to be regulated, in part, by NO-mediated inhibition of the NF-κB survival/anti-apoptotic pathways and downstream of NF-κB by inhibition of the transcription factor Yin Yang 1 (YY1). In addition to NO-induced sensitization to apoptosis, we have also shown that NO induced the expression of the metastasis-suppressor/immunosurveillance cancer gene product, Raf-1 kinase inhibitor protein (RKIP). Overexpression of RKIP mimics NO in tumor cells-induced sensitization to apoptosis. The induction of RKIP by NO was the result of the inhibition of the RKIP repressor, Snail, downstream of NF-κB. These findings established the presence of a dysregulated NF-κB/Snail/YY1/ RKIP circuitry in resistance and that treatment with NO modifies this loop in tumor cells in favor of the inhibition of tumor cell survival and the response to cytotoxic drugs. Noteworthy, the NF-κB/Snail/YY1/RKIP loop consists of gene products that regulate the epithelial to mesenchymal transition (EMT) and, thus, tumor metastasis. Hence, we have found that treatment of metastatic cancer cell lines with DETANONOate inhibited the EMT phenotype, through both the inhibition of the metastasis-inducers, NF-κB and Snail and the induction of the metastasis-suppressor, RKIP. Altogether, the above findings establish, for the first time, the dual role of high levels of NO in the sensitization of tumor cells to apoptotic stimuli as well as inhibition of EMT. Hence, NO donors may be considered as novel potential therapeutic agents with dual roles in the treatment of patients with refractory cancer and in the prevention of the initiation of the metastatic cascade via EMT.
已有多项研究表明一氧化氮（NO）在调节肿瘤细胞行为方面发挥着重要作用，并表明 NO 既促进又抑制肿瘤发生。这些相互矛盾的发现部分归因于所使用的 NO 水平，即低水平促进肿瘤生长，高水平抑制肿瘤生长。我们的研究主要集中在使用主要由一氧化氮供体 DETANONOate 提供的高水平 NO 上。我们已经表明，用 DETANONOate 处理耐药肿瘤细胞可通过化疗药物和细胞毒性免疫治疗配体使它们对细胞凋亡敏感。NO 使肿瘤细胞对细胞凋亡敏感的潜在机制部分受到调节，这是由于 NO 介导的抑制 NF-κB 存活/抗凋亡途径以及 NF-κB 下游转录因子 Yin Yang 1（YY1）的抑制。除了 NO 诱导的细胞凋亡敏感性外，我们还表明，NO 诱导了转移抑制/免疫监视癌症基因产物 Raf-1 激酶抑制剂蛋白（RKIP）的表达。RKIP 的过表达模拟了肿瘤细胞中 NO 诱导的细胞凋亡敏感性。NO 诱导 RKIP 的原因是 NF-κB 下游 RKIP 抑制剂 Snail 的抑制。这些发现证实了耐药性中存在失调的 NF-κB/Snail/YY1/RKIP 电路，并且用 NO 治疗可改变肿瘤细胞中的这种循环，有利于抑制肿瘤细胞存活和对细胞毒性药物的反应。值得注意的是，NF-κB/Snail/YY1/RKIP 循环由调节上皮间质转化（EMT）的基因产物组成，因此与肿瘤转移有关。因此，我们发现用 DETANONOate 处理转移性癌细胞系可通过抑制转移诱导剂 NF-κB 和 Snail 的表达以及诱导转移抑制剂 RKIP 的表达来抑制 EMT 表型。总而言之，上述发现首次确立了高水平 NO 在肿瘤细胞对凋亡刺激敏感以及抑制 EMT 中的双重作用。因此，NO 供体可被视为新型潜在治疗剂，在治疗难治性癌症患者和通过 EMT 预防转移级联的启动方面具有双重作用。
