Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide

PLoS One. 2014 Jun 6;9(6):e99378. doi: 10.1371/journal.pone.0099378. eCollection 2014.

Abstract

Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / biosynthesis*
  • Activating Transcription Factor 4 / genetics
  • Fibrosis / drug therapy
  • Fibrosis / genetics
  • Fibrosis / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Knockdown Techniques
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Receptors, Nerve Growth Factor / biosynthesis*
  • Receptors, Nerve Growth Factor / genetics
  • Safrole / analogs & derivatives*
  • Safrole / pharmacology
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics

Substances

  • ATF4 protein, human
  • CXCL8 protein, human
  • Interleukin-8
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Receptors, Nerve Growth Factor
  • Activating Transcription Factor 4
  • safrole oxide
  • Safrole

Grants and funding

This work was supported by National Natural Science Foundation of China (No. 30800398 and 81021001 http://isisn.nsfc.gov.cn/egrantweb/); Science Foundation for the Excellent Youth Scholars of Ministry of Education of China (No. 200804221004 http://www.moe.edu.cn/publicfiles/business/htmlfiles/moe/moe_257/index.html) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.