Decorin protein core inhibits in vivo cancer growth and metabolism by hindering epidermal growth factor receptor function and triggering apoptosis via caspase-3 activation

Daniela G. Seidler, Silvia Goldoni, Christopher Agnew, Christopher Cardi, Mathew L. Thakur, Rick T. Owens, David J. McQuillan, Renato V. Iozzo*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

137 Citations (Scopus)

Abstract

Decorin is not only a regulator of matrix assembly but also a key signaling molecule that modulates the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR). Decorin evokes protracted internalization of the EGFR via a caveolar-mediated endocytosis, which leads to EGFR degradation and attenuation of its signaling pathway. In this study, we tested if systemic delivery of decorin protein core would affect the biology of an orthotopic squamous carcinoma xenograft. After tumor engraftment, the animals were given intraperitoneal injections of either vehicle or decorin protein core (2.5-10 mg kg(-1)) every 2 days for 18-38 days. This regimen caused a significant and dose-dependent inhibition of the tumor xenograft growth, with a concurrent decrease in mitotic index and a significant increase in apoptosis. Positron emission tomography showed that the metabolic activity of the tumor xenografts was significantly reduced by decorin treatment. Decorin protein core specifically targeted the tumor cells enriched in EGFR and caused a significant downregulation of EGFR and attenuation of its activity. In vitro studies showed that the uptake of decorin by the A431 cells was rapid and caused a protracted down-regulation of the EGFR to levels similar to those observed in the tumor xenografts. Furthermore, decorin induced apoptosis via activation of caspase-3. This could represent an additional mechanism whereby decorin might influence cell growth and survival.

Original languageEnglish
Pages (from-to)26408-26418
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number36
DOIs
Publication statusPublished - 8 Sep 2006

Keywords

  • DOWN-REGULATION
  • SIGNAL-TRANSDUCTION
  • GENE-EXPRESSION
  • LEUCINE-RICH PROTEOGLYCANS
  • EGF-RECEPTOR
  • TYROSINE KINASES
  • CHICK-EMBRYO FIBROBLASTS
  • CELL-GROWTH
  • CARCINOMA-CELLS
  • CYCLIN-DEPENDENT KINASES

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