NQO1 suppresses NF-κB-p300 interaction to regulate inflammatory mediators associated with prostate tumorigenesis.
NQO1 suppresses NF-κB-p300 interaction to regulate inflammatory mediators associated with prostate tumorigenesis.
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DOI：
10.1158/0008-5472.can-14-0562
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Ghosh R
中科院分区：
文献类型：
--
作者：
Thapa D;Meng P;Bedolla RG;Reddick RL;Kumar AP;Ghosh R
根据对NQO1缺陷小鼠的研究，NADPH还原酶NQO1是维持细胞抗氧化剂库所必需的，这种酶可能有助于肿瘤的发生。在这项工作中，我们试图更深入地了解NQO1如何促进前列腺癌的发生，在这种情况下，氧化应激和炎症是疾病发展和进展的既定贡献者。在TRAMP小鼠前列腺癌模型中，NQO1在肿瘤细胞中高表达。前列腺癌细胞中NQO1的沉默增加了核IKK-α和NF-κB的水平，同时降低了P53的水平，导致了NF-κB和p300之间的相互作用，从而加强了生存信号。基因表达分析显示，在NQO1减弱的细胞中，与炎症和肿瘤发生相关的一系列免疫相关转录物上调，IL-8在细胞培养中被证实为NQO1支持的关键细胞因子。值得注意的是，NQO1沉默的前列腺癌细胞对雄激素剥夺更具抵抗力。此外，抑制NQO1增加了迁移，包括在雄激素剥夺的情况下。这些结果揭示了前列腺癌中NQO1的表达和促炎细胞因子信号之间的分子联系。此外，我们的结果表明，通过抑制NQO1改变氧化还原稳态可能通过对NF-κB和P53功能的相反作用促进雄激素非依赖性细胞的存活。
NADPH reductase NQO1 is needed to maintain a cellular pool of antioxidants and this enzyme may contribute to tumorigenesis, on the basis of studies in NQO1-deficient mice. In this work, we sought deeper insights into how NQO1 contributes to prostate carcinogenesis, a setting where oxidative stress and inflammation are established contributors to disease development and progression. In the TRAMP mouse model of prostate cancer, NQO1 was highly expressed in tumor cells. NQO1 silencing in prostate cancer cells increased levels of nuclear IKK-α and NF-κB while decreasing the levels of p53, leading to interactions between NF-κB and p300 that reinforce survival signaling. Gene expression analysis revealed upregulation of a set up immune-associated transcripts associated with inflammation and tumorigenesis in cells where NQO1 was attenuated, with IL-8 confirmed functionally in cell culture as one key NQO1-supported cytokine. Notably, NQO1-silenced prostate cancer cells were more resistant to androgen deprivation. Further, NQO1 inhibition increased migration including under conditions of androgen deprivation. These results reveal a molecular link between NQO1 expression and pro-inflammatory cytokine signaling in prostate cancer. Further, our results suggest that altering redox homeostasis through NQO1 inhibition might promote androgen-independent cell survival via opposing effects on NF-κB and p53 function.