NF-E2-related factor 2 (Nrf2) is a transcription factor and a pivotal factor in the induction of the cell defense system. Recent reports show that Nrf2 plays critical roles in tumor heterogeneity and drug resistance. In the present study we investigated whether and how Nrf2 mediated the resistance of human cancer cells to boningmycin (BON), a new antitumor antibiotic of the bleomycin family. We showed that in the expression levels of Nrf2 in human non-small lung cancer A549 cells were much higher than those in human hepatoblastoma HepG2 cells, and their resistance to BON was opposite to Nrf2 expression (the IC₅₀values of BON in A549 cells and HepG2 cells were 5.97 and 0.61 μmol/L, respectively). Similar results were observed with the anticancer agent cisdiamminedichloroplatinum (DDP), which was used as a positive control. In A549 cells, Nrf2 mRNA knockdown significantly increased their susceptibilities to BON and DDP. An enhanced resistance to BON and DDP was observed in HepG2 cells after overexpression of the wild-type Nrf2 protein. Treatment with a specific Nrf2 inhibitor, luteolin, significantly sensitized A549 cells to BON and DDP and increased BON- or DDP-induced apoptosis. The total levels of glutathione (GSH), the final product of the Nrf2 signaling pathway, were much higher in A549 cells than those in HepG2 cells. Supplementation of GSH in HepG2 cells significantly decreased their susceptibility to BON and DDP, wheras depleting GSH with the specific inhibitor L-buthionine sulfoximine in A549 cells significantly increased their susceptibility to BON and DDP. Our results demonstrate that Nrf2 mediates the resistance to BON through regulating glutathione levels in A549 cells and HepG2 cells.

中文翻译：

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Nrf2可通过调节谷胱甘肽水平在体外介导人类A549和HepG2癌细胞对新型抗肿瘤抗生素博宁霉素的耐药性。

NF-E2相关因子2（Nrf2）是转录因子和细胞防御系统诱导中的关键因子。最近的报道表明，Nrf2在肿瘤异质性和耐药性中起关键作用。在本研究中，我们调查了Nrf2是否以及如何介导人类癌细胞对博来霉素（BON）（博来霉素家族的一种新型抗肿瘤抗生素）的抗性。我们发现人非小肺癌A549细胞中Nrf2的表达水平远高于人肝母细胞瘤HepG2细胞中的Nrf2表达水平，并且它们对BON的抗性与Nrf2表达相反（IC ₅₀A549细胞和HepG2细胞的BON值分别为5.97和0.61μmol/ L）。使用抗癌药顺二氨二氯铂（DDP）作为阳性对照，观察到了相似的结果。在A549细胞中，Nrf2 mRNA敲低显着增加了其对BON和DDP的敏感性。野生型Nrf2蛋白过表达后，在HepG2细胞中观察到对BON和DDP的增强抗性。用特定的Nrf2抑制剂木犀草素处理，可使A549细胞对BON和DDP明显敏感，并增加BON或DDP诱导的细胞凋亡。Nrf2信号通路的最终产物谷胱甘肽（GSH）的总水平在A549细胞中比在HepG2细胞中高得多。HepG2细胞中补充GSH可以显着降低其对BON和DDP的敏感性，在A549细胞中用特异性抑制剂L-丁硫氨酸亚砜消灭GSH的乳清显着增加了其对BON和DDP的敏感性。我们的结果表明，Nrf2通过调节A549细胞和HepG2细胞中的谷胱甘肽水平来介导对BON的抗性。