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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / toxicity*
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / metabolism
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Kelch-Like ECH-Associated Protein 1
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Liver Neoplasms / etiology*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Marine Toxins
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Microcystins / chemistry
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Microcystins / toxicity*
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NAD(P)H Dehydrogenase (Quinone) / genetics
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NAD(P)H Dehydrogenase (Quinone) / metabolism
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NF-E2-Related Factor 2 / antagonists & inhibitors
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism*
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Protein Binding
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RNA Interference
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RNA, Small Interfering / metabolism
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Up-Regulation
Substances
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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Marine Toxins
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Microcystins
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NF-E2-Related Factor 2
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RNA, Small Interfering
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HMOX1 protein, human
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Heme Oxygenase-1
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NAD(P)H Dehydrogenase (Quinone)
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NQO1 protein, human
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cyanoginosin LR