摘要
Chemoprevention failure is considered to be the most emerging problem that makes non-small cell lung cancer (NSCLC) as one of the deadliest malignancies in the world. In NSCLC cells, Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, promotes cancer cell survival and fosters mechanism for drug resistance. Here we report identification of Kaempferol, a dietary flavonoid, as a potent Nrf2 inhibitor using Nrf2 reporter assay in NSCLC cells (A549 and NCIH460). Kaempferol selectively reduces Nrf2 mRNA and protein levels and lower level of nuclear Nrf2 downregulates transcription of Nrf2 target genes (NQO1, HO1, AKR1C1 and GST). Kaempferol (25 μM) mediated downregulation of GST, NQO1 and HO1 expression is also observed even after stimulation of Nrf2 by tert-butylhydroquinone (tBHQ). Again, Kaempferol incubation does not change the levels of NFκBp65 and phospho NFκBp65, suggesting it hampers Nrf2 signalling pathway in these cells. Nrf2 inhibition by Kaempferol induces ROS accumulation after 48 h of treatment and makes NSCLC cells sensitive to apoptosis at physiological concentration. Taken together, our study demonstrates that Kaempferol is a potent inhibitor of Nrf2 and can be used as a natural sensitizer and anti-cancer agent for lung cancer therapeutics.
摘要译文
化学预防失败被认为是使非小细胞肺癌（NSCLC）成为世界上最致命的恶性肿瘤之一的最新出现的问题。在NSCLC细胞中，核因子红细胞2相关因子2（Nrf2）是一种氧化还原敏感的转录因子，可促进癌细胞存活并建立耐药性机制。在这里，我们报告了使用Nrf2报告基因检测法在非小细胞肺癌细胞（A549和NCIH460）中鉴定出一种有效的Nrf2抑制剂，即一种膳食类黄酮山emp酚。山emp酚选择性降低Nrf2 mRNA和蛋白水平，降低核Nrf2水平下调Nrf2靶基因（NQO1，HO1，AKR1C1和GST）的转录。即使在叔丁基对苯二酚（tBHQ）刺激Nrf2后，Kaempferol（25μM）也会下调GST，NQO1和HO1表达。同样，山奈酚的孵育不会改变NFκBp65和磷酸化NFκBp65的水平，表明它阻碍了这些细胞中的Nrf2信号传导途径。山emp酚对Nrf2的抑制作用在处理48小时后诱导ROS积累，并使NSCLC细胞在生理浓度下对细胞凋亡敏感。两者合计，我们的研究表明山emp酚是Nrf2的有效抑制剂，可以用作肺癌治疗剂的天然敏化剂和抗癌剂。
ChandraniFouzder;AlpanaMukhuty;RakeshKundu. Kaempferol inhibits Nrf2 signalling pathway via downregulation of Nrf2 mRNA and induces apoptosis in NSCLC cells[J]. Archives of Biochemistry and Biophysics, 2021,697