State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, CAS, Wuhan 430072, People's Republic of China.
Chem Res Toxicol. 2010 Sep 20;23(9):1477-84. doi: 10.1021/tx1001628.
Microcystin-LR (MC-LR) is a potent heptapeptide hepatotoxin at high doses, but its underlying mechanism of promoting liver cell proliferation at low doses is unclear. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is key in mediating the protective antioxidant response against various environmental toxicants, but emerging data suggest that constitutive activation of Nrf2 contributes to a malignant phenotype. The purpose of this study was to characterize the interactions and effects of Nrf2 activation on cell proliferation induced by MC-LR treatment. Treatment of HepG2 and Hep3B cells with MC-LR resulted in significant increases in Nrf2-ARE binding activities in the nuclear fractions and upregulation of its downstream genes HO-1 and NQO1. A possible mechanism may be that MC-LR binds to the cytosolic regulator protein Keap1 to liberate Nrf2. Nrf2 knockdown inhibited MC-LR-induced cell proliferation and cell cycle progression. Together, these results indicate that MC-LR-induced upregulation of Nrf2 in cancer cells promotes liver cancer cell growth and suggest a positive role of Nrf2 in tumorigenesis.
微囊藻毒素-LR（MC-LR）是一种在高剂量下具有强烈肝毒性的七肽，但其在低剂量下促进肝细胞增殖的潜在机制尚不清楚。转录因子核因子红细胞 2 相关因子 2（Nrf2）是介导针对各种环境毒物的保护性抗氧化反应的关键，但新出现的数据表明，Nrf2 的组成性激活有助于恶性表型。本研究旨在描述 Nrf2 激活与 MC-LR 处理诱导的细胞增殖之间的相互作用和影响。用 MC-LR 处理 HepG2 和 Hep3B 细胞导致核部分 Nrf2-ARE 结合活性显著增加，以及其下游基因 HO-1 和 NQO1 的上调。一种可能的机制可能是 MC-LR 与细胞质调节剂蛋白 Keap1 结合，从而释放 Nrf2。Nrf2 敲低抑制了 MC-LR 诱导的细胞增殖和细胞周期进程。总之，这些结果表明，MC-LR 诱导癌细胞中 Nrf2 的上调促进肝癌细胞生长，并提示 Nrf2 在肿瘤发生中具有积极作用。
