Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo.
The small leucine-rich proteoglycan decorin interacts with the epidermal growth factor receptor (EGFR) and triggers a signaling cascade that leads to elevation of endogenous p21 and growth suppression. We demonstrate that decorin causes a sustained down-regulation of the EGFR. Upon stable expression of decorin, the EGFR number is reduced by approximately 40%, without changes in EGFR expression. However, EGFR phosphorylation is nearly completely abolished. Concurrently, decorin attenuates the EGFR-mediated mobilization of intracellular calcium and blocks the growth of tumor xenografts by down-regulating the EGFR kinase in vivo. Thus, decorin acts as an autocrine and paracrine regulator of tumor growth and could be utilized as an effective anti-cancer agent.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
G
G
Csordás
M
M
Santra
C C
CC
Reed
I
I
Eichstetter
D J
DJ
McQuillan
D
D
Gross
M A
MA
Nugent
G
G
Hajnóczky
R V
RV
Iozzo
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000628:therapy*; D002455:Cell Division; D058575:Decorin; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011509:Proteoglycans / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D002118:Calcium