Activation of Nrf2 by microcystin-LR provides advantages for liver cancer cell growth

Chem Res Toxicol. 2010 Sep 20;23(9):1477-84. doi: 10.1021/tx1001628.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / toxicity*
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • Liver Neoplasms / etiology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Marine Toxins
  • Microcystins / chemistry
  • Microcystins / toxicity*
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Up-Regulation

Substances

  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Marine Toxins
  • Microcystins
  • NF-E2-Related Factor 2
  • RNA, Small Interfering
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • cyanoginosin LR