Native and iron-saturated bovine lactoferrin differently hinder migration in a model of human glioblastoma by reverting epithelial-to-mesenchymal transition-like process and inhibiting interleukin-6/STAT3 axis

Cell Signal. 2020 Jan:65:109461. doi: 10.1016/j.cellsig.2019.109461. Epub 2019 Nov 1.

Abstract

Glioblastoma, the most lethal form of brain cancer, is characterized by fast growth, migration and invasion of the surrounding parenchyma, with epithelial-to-mesenchymal transition (EMT)-like process being mostly responsible for tumour spreading and dissemination. A number of actors, including cadherins, vimentin, transcriptional factors such as SNAIL, play critical roles in the EMT process. The interleukin (IL)-6/STAT3 axis has been related to enhanced glioblastoma's migration and invasion abilities as well. Here, we present data on the differential effects of native and iron-saturated bovine lactoferrin (bLf), an iron-chelating glycoprotein of the innate immune response, in inhibiting migration in a human glioblastoma cell line. Through a wound healing assay, we found that bLf was able to partially or completely hinder cell migration, depending on its iron saturation rate. At a molecular level, bLf down-regulated both SNAIL and vimentin expression, while inducing a notable increase in cadherins' levels and inhibiting IL-6/STAT3 axis. Again, these effects positively correlated to bLf iron-saturation state, with the Holo-form resulting more efficient than the native one. Overall, our data suggest that bLf could represent a novel and efficient adjuvant treatment for glioblastoma's standard therapeutic approaches.

Keywords: Bovine lactoferrin; Epithelial to mesenchymal transition; Glioblastoma; Interleukin-6; STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / metabolism*
  • Humans
  • Interleukin-6 / metabolism*
  • Iron / metabolism*
  • Lactoferrin / chemistry
  • Lactoferrin / metabolism
  • Lactoferrin / pharmacology*
  • STAT3 Transcription Factor / metabolism*
  • Snail Family Transcription Factors / metabolism
  • Up-Regulation
  • Vimentin / metabolism

Substances

  • Cadherins
  • Interleukin-6
  • SNAI1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Snail Family Transcription Factors
  • Vimentin
  • Iron
  • Lactoferrin