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A more recent version of this article appeared on September 8, 2006
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M602853200v1
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Papers In Press, published online ahead of print July 11, 2006
J. Biol. Chem, 10.1074/jbc.M602853200
Submitted on March 27, 2006
Revised on July 5, 2006
Accepted on July 11, 2006

Decorin protein core inhibits in vivo cancer growth and metabolism by hindering EGF 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, and Renato V. Iozzo

Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107

Corresponding Author: iozzo{at}mail.jci.tju.edu

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 two days for 18 to 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 down-regulation 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.


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