Decorin Antagonizes Met Receptor Activity and Down-regulates β-Catenin and Myc Levels

Abstract

A theme emerging during the past few years is that members of the small leucine-rich proteoglycan gene family affect cell growth by interacting with multiple receptor tyrosine kinases (RTKs), mostly by a physical down-regulation of the receptors, thereby depriving tumor cells of pro-survival signals. Decorin binds and down-regulates several RTKs, including Met, the receptor for hepatocyte growth factor. Here we demonstrate that decorin blocks several biological activities mediated by the Met signaling axis, including cell scatter, evasion, and migration. These effects were mediated by a profound down-regulation of noncanonical ␤-catenin levels. In addition, Myc, a downstream target of ␤-catenin, was markedly down-regulated by decorin, whereas phosphorylation of Myc at threonine 58 was markedly induced. The latter is known to destabilize Myc and target it for proteasomal degradation. We also discovered that systemic delivery of decorin using three distinct tumor xenograft models caused down-regulation of Met and a concurrent suppression of ␤-catenin and Myc levels. We found that decorin protein core labeled with the near infrared dye IR800 specifically targeted the tumor cells expressing Met. Even 68-h post-injection, decorin was found to reside within the tumor xenografts with little or no binding to other tissues. Collectively, our results indicate a role for a secreted proteoglycan in suppressing the expression of key oncogenic factors required for tumor progression.Biological activities are triggered, modulated, and maintained mostly by the complex interplay among extracellular matrix molecules, multifunctional growth factors, and their surface receptors (1). Genetic and biochemical studies have revealed that many of the matrix components are indeed signaling molecules that can affect the behavior of cells during development and disease progression (2). Decorin, a prototype member of the small leucine-rich proteoglycans (SLRPs) 3 (3-8), is involved in a multitude of biological processes including collagen fibrillogenesis (9 -12), modulation of various growth factors and receptors (13-22), renal diseases (23-25), angiogenesis (26, 27), wound healing (28), myocardial infarction (29), lung and tendon mechanics (30 -32), infectious diseases (33, 34), bone and tooth development (35, 36), connective tissue development (37-41), and bone marrow stromal cell biology (42).The involvement of decorin in cancer progression has been demonstrated in mutant mice. Although the decorin-null mice do not spontaneously develop malignant neoplasms, mice carrying a targeted deletion of both decorin and the tumor suppressor p53 succumb within 3-4 months to aggressive lymphomas at a rate faster than p53-null mice alone (43), suggesting that decorin is permissive for tumorigenesis. In accordance with this study, ϳ30% of decorin-null animals, which were backcrossed into a different genetic background, displayed spontaneous occurrence of intestinal tumors, and both the tumor burden and frequency were enhanced by subjecting the mutant mi...

Calcium Efflux Activity of Plasma Membrane Ca2+ ATPase-4 (PMCA4) Mediates Cell Cycle Progression in Vascular Smooth Muscle Cells

“…Decorin can inhibit EGFR, has been implicated in G 1 phase arrest (by inducing p21 expression), and is deregulated in many types of human cancers (23,24,40). Decorin is also known to inhibit the VSMC cell cycle by triggering Myc degradation (41) and can also inhibit FosL1 (42). Under normal conditions FosL1 and Jun dimerize to form AP-1, which can induce the NFAT family of transcription factors (43), leading to cyclin D1 expression (26).…”

Decorin causes autophagy in endothelial cells via Peg3

“…Our main hypothesis is that decorin functions as an endogenous soluble inhibitor of cancer growth and angiogenesis (17)(18)(19)(20)(21). Collectively, these properties are critical for decorin to act as a potent tumoricidal agent, as demonstrated conclusively by systemically administered decorin labeled with IR-Dye 800 avidly, specifically, and stably targeting orthotopic tumor xenografts (22). Moreover, decorin is capable of significantly inhibiting neovascularization of triplenegative basal cell breast carcinomas (23).…”

Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

“…16 Recent studies have also shown that decorin is an antagonistic ligand of the Met receptor. 17,18 Molecular modeling indicates that truncation of the decorin C-terminus in human CSCD affects the ear repeat, which is proposed to maintain the conformation of the protein and to regulate ligand binding. 8 However, the dysfunctional role of mutant decorin in human autosomal-dominant CSCD and the pathophysiological basis of this inherited disease remains to be elucidated.…”