Activation of Nrf2 by microcystin-LR provides advantages for liver cancer cell growth.
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.
Gan
Nanqin
N
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, CAS, Wuhan 430072, People's Republic of China.
Sun
Xiaoyun
X
Song
Lirong
L
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008387:Marine Toxins; D052998:Microcystins / Q000737:chemistry / Q000633:toxicity*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008387:Marine Toxins; D052998:Microcystins; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C057862:cyanoginosin LR