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

Academic Article

Abstract

  • 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.
  • Published In

  • Oncogene  Journal
  • Keywords

  • Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Survival, Humans, Inverted Repeat Sequences, NF-E2-Related Factor 2, Neoplasms, Phosphorylation, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Smad Proteins, Transcription, Genetic, ras Proteins
  • Digital Object Identifier (doi)

    Author List

  • Rachakonda G; Sekhar KR; Jowhar D; Samson PC; Wikswo JP; Beauchamp RD; Datta PK; Freeman ML
  • Start Page

  • 3703
  • End Page

  • 3714
  • Volume

  • 29
  • Issue

  • 25