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Activation of Nrf2 by microcystin-LR provides advantages for liver cancer cell growth
Nanqin Gan1, Xiaoyun Sun, Lirong Song
1State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, CAS, Wuhan 430072, People's Republic of China.
Abstract:
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.
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