Wogonin reversed resistant human myelogenous leukemia cells via inhibiting Nrf2 signaling by Stat3/NF-κB inactivation.
Wogonin reversed resistant human myelogenous leukemia cells via inhibiting Nrf2 signaling by Stat3/NF-κB inactivation.
复制标题
汉黄芩素通过 Stat3/NF-kappaB 失活抑制 Nrf2 信号传导，逆转耐药人骨髓性白血病细胞
DOI：
10.1038/srep39950
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发表时间：
2017-02-02
影响因子：
4.6
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Xu X;Zhang X;Zhang Y;Yang L;Liu Y;Huang S;Lu L;Kong L;Li Z;Guo Q;Zhao L
最近据报道，组成型 NF-E2 相关因子 2（Nrf2、NFE2L2）激活在增强许多肿瘤中的细胞存活和抗癌药物耐药性方面发挥着关键作用。汉黄芩素通过减少阿霉素（ADR）诱导的耐药人慢性粒细胞白血病（CML）K562/A02中的Nrf2 mRNA而具有很强的逆转作用，但减少Nrf2 mRNA的机制仍不清楚。在本研究中，我们旨在阐明汉黄芩素抑制耐药CML细胞中Nrf2转录的机制，并进一步评估汉黄芩素对已建立的动物模型的逆转作用。数据表明汉黄芩素通过 NF-κB 失活抑制 Nrf2 的转录。汉黄芩素通过抑制 κB 结合活性来抑制 p65 与 Nrf2 的结合。进一步的研究表明，κB2 位点是汉黄芩素在耐药 K562 细胞中降低 Nrf2 的原因。此外，pY705-Stat3 的减少涉及汉黄芩素对 p65 与 Nrf2 结合的抑制。在体内，汉黄芩素通过抑制 pY705-Stat3 和 Nrf2 信号传导增强 ADR 对白血病发展的抑制作用。综上所述，这些结果证明汉黄芩素可以通过Stat3/NF-κB信号抑制Nrf2来有效对抗化疗耐药，并支持汉黄芩素可以开发为治疗耐药人骨髓性白血病的有效天然增敏剂。
Constitutive NF-E2-related factor 2 (Nrf2, NFE2L2) activation has been recently reported to play a pivotal role in enhancing cell survival and resistance to anticancer drugs in many tumors. Wogonin had strong reversal potency via reduction of Nrf2 mRNA in Adriamycin (ADR)-induced resistant human chronic myelogenous leukemia (CML) K562/A02, but the mechanism of reduction of Nrf2 mRNA was still unclear. In this study, we aimed to delineate the mechanism by which Wogonin suppressed transcription of Nrf2 in resistant CML cells and further evaluate the reversal effects of Wogonin on the established animal models. Data indicated that Wogonin suppressed transcription of Nrf2 by NF-κB inactivation. Wogonin inhibited the binding of p65 to Nrf2 by suppression of the κB-binding activity. Further research revealed the κB2 site was responsible for the decreased Nrf2 by Wogonin in resistant K562 cells. Furthermore, reduction of pY705-Stat3 was involved in inhibition of the binding of p65 to Nrf2 by Wogonin. In vivo, Wogonin potentiated the inhibitory effect of ADR on leukemia development by suppressing pY705-Stat3 and Nrf2 signaling. In summary, these results demonstrated Wogonin could combat chemoresistance effectively through inhibiting Nrf2 via Stat3/NF-κB signaling, and supported that Wogonin can be developed into an efficient natural sensitizer for resistant human myelogenous leukemia.