Decorin Protein Core Inhibits in Vivo Cancer Growth and Metabolism by Hindering Epidermal Growth Factor Receptor Function and Triggering Apoptosis via Caspase-3 Activation

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.The growth of human cancer cells is often dependent or facilitated by the overexpression of receptor tyrosine kinase, such as the EGFR, 2 that provide a growth advantage to the growing and infiltrating neoplasms (1). To prevent the dire consequences of uncontrolled activation of EGFR, a number of negative feedback mechanisms, both extracellular and intracellular, have evolved (2, 3). The prominent role of the EGFR as a crucial relay station among various inputs from the environment and cellular responses has raised the significance of this signaling-transducing receptor to a new level and offers new possibilities for therapeutic intervention (4). We have previously shown that decorin, a secreted small leucine-rich proteoglycan (5, 6), is capable of suppressing the growth of tumor cells with various histogenetic backgrounds (7, 8) by directly interacting with the EGFR (9 -11). Decorin evokes a protracted down-regulation of EGFR tyrosine kinase (12) and other members of the ErbB family of receptor tyrosine kinase (13) and causes an attenuation of the EGFR-mediated mobilization of intracellular calcium (12). Decorin induces expression of the endogenous cyclin-dependent kinase inhibitor p21 WAF1 (14, 15) and a subsequent arrest of the cells in the G 1 phase of the cell cycle (7). These growthsuppressive properties of the soluble decorin and its protein core can also affect murine tumor cells (8) and normal human cells, such as endothelial cells (16) and macrophages (17). A number of observations point toward a key role for decorin in the cont...

Influence of cyclic strain and decorin deficiency on 3D cellularized collagen matrices

“…In addition, the cyclically strained collagen gels seeded with Dcn −/− cells contained the greatest final density of cells, as shown in our previous study [16]. It has been widely recognized that decorin can inhibit cell proliferation, both by sequestering TGF-β and by blocking the epidermal growth factor receptor [26][27][28][29][30].…”

Decorin causes autophagy in endothelial cells via Peg3

“…Notably, Peg3 has been shown to regulate p53-mediated apoptosis by interacting directly with the Seven in absentia homolog 1 (Siah1a) (57) and by inducing Bcl2-associated X (Bax) translocation from the cytosol to mitochondria (58). Thus, it is plausible that decorin might affect this pathway in endothelial cells also, because we have shown previously that decorin induces apoptosis in carcinoma cells by activating caspase 3 (59).…”

NG2, a novel proapoptotic receptor, opposes integrin α4 to mediate anoikis through PKCα-dependent suppression of FAK phosphorylation

“…Other proteoglycans, including syndecan-2 and syndecan-4, decorin, biglycan, CD44, and heparan sulfate proteoglycans promote or block apoptosis by modulating growth factor or integrin receptor function or by altering cell aggregation or specific signaling networks. [22][23][24][25] NG2 also modulates growth factor receptor and integrin function to regulate a variety of cellular processes. 17,26 In addition, NG2 and integrin a4 act as coreceptors in focal contact formation and spreading of melanoma.…”

“…NG2 cDNA (pcDNAamp/NG2) has been described. 25,35 NG2 siRNA and mutant control NG2 siRNA were transcribed in vitro with chemically synthesized DNA oligonucleotides and T7 RNA polymerase as described. 36 Synthesis and annealing were confirmed by non-denaturing PAGE.…”