Increased cell migration and plasticity in Nrf2-deficient cancer cell lines

Oncogene. 2010 Jun 24;29(25):3703-14. doi: 10.1038/onc.2010.118. Epub 2010 May 3.


Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression is deregulated in many cancers. Genetic and biochemical approaches coupled with functional assays in cultured cells were used to explore the consequences of Nrf2 repression. Nrf2 suppression by Keap1-directed ubiquitylation or the expression of independent short hairpin RNA (shRNA)/siRNA sequences enhanced cellular levels of reactive oxygen species, Smad-dependent tumor cell motility and growth in soft agar. Loss of Nrf2 was accompanied by concomitant Smad linker region/C-terminus phosphorylation, induction of the E-cadherin transcriptional repressor Slug and suppression of the cell-cell adhesion protein E-cadherin. Ectopic expression of the wildtype but not dominant-negative Nrf2 suppressed the activity of a synthetic transforming growth factor-beta1-responsive CAGA-directed luciferase reporter. shRNA knock-down of Nrf2 enhanced the activity of the synthetic CAGA reporter, as well as the expression of the endogenous Smad target gene plasminogen activator inhibitor-1. Finally, we found that Nrf2/Smad3/Smad4 formed an immunoprecipitable nuclear complex. Thus, loss of Nrf2 increased R-Smad phosphorylation and R-Smad signaling, supporting the hypothesis that loss of Nrf2 in an oncogenic context-dependent manner can enhance cellular plasticity and motility, in part by using transforming growth factor-beta/Smad signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cell Movement* / genetics
  • Cell Survival / genetics
  • Humans
  • Inverted Repeat Sequences
  • NF-E2-Related Factor 2 / deficiency*
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Smad Proteins / metabolism
  • Transcription, Genetic
  • ras Proteins / metabolism


  • NF-E2-Related Factor 2
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Smad Proteins
  • ras Proteins