Decorin-mediated oncosuppression - a potential future adjuvant therapy for human epithelial cancers

Abstract

Currently, the multifaceted role of the extracellular matrix (ECM) in tumourigenesis has been realized. One ECM macromolecule exhibiting potent oncosuppressive actions in tumourigenesis is decorin, the prototype of the small leucine-rich proteoglycan gene family. The actions of decorin include its ability to function as an endogenous pan-receptor tyrosine kinase inhibitor, a regulator of both autophagy and mitophagy, as well as a modulator of the immune system. In this review, we will discuss these topics in more detail. We also provide a summary of preclinical studies exploring the value of decorin-mediated oncosuppression, as a potential future adjuvant therapy for epithelial cancers. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

Figure 1

Schematic structure of decorin. The decorin core protein comprises four domains, shown as I–IV. Domain I is the signal peptide and the propeptide‐containing domain which is cleaved before decorin can be secreted into the ECM. Domain II (rich in cysteine residues) is the domain where the single GAG side‐chain (either chondroitin sulfate or dermatan sulfate) is attached to Ser⁴. Domain III (characteristic of decorin) consists of 12 tandem LRRs and up to three N‐linked oligosaccharides. Similar to domain II, the carboxy terminal domain (domain IV) contains two cysteine residues. There are two disulfide bridges on the N‐terminal side, and one on the C‐terminal side (not shown in figure). Both the LRR domain (domain III) and the single GAG side chain are primarily responsible for decorin's multiple interactions with other molecules, the LRR domain being crucial for decorin‐protein interactions. C, cysteine residue.

Figure 2

Various molecular categories of decorin's interactions. The groups are modified from the analysis performed by Gubbiotti et al. (2016), where they identified decorin‐binding ligands in the literature and in different interaction databases including MatrixDB (http://matrixdb.univ‐lyon1.fr/). Representative examples of proteins in each different category are as follows: intracellular proteins (filamin A, tyrosine 3‐monooxygenase and zinc finger, and BTB domain containing 33); hormones, (anti)‐coagulation factors, immune‐related and carrier proteins (insulin, tissue‐type plasminogen activator, von Willebrand factor and LDL); enzymes (matrix metalloproteinase 2, 3 and 7); membrane proteins (EGF receptors 1, 2 and 4; IGF‐IR; hepatocyte growth factor receptor; and TLRs 2 and 4); growth factors (TGFβ‐1 and ‐2, and FGF‐1, −2, −7 and −8); and ECM proteins, PGs and matricellular proteins (collagens I–VI, perlecan, fibronectin and thrombospondin 1). The X‐axis indicates the number of molecules (n) in each category. For more details of the various categories, see the reference above. PGs, proteoglycans.

Figure 3

Decorin in cancer, based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (http://www.genome.jp/kegg‐bin/show_pathway?hsa05205). This pathway map presents representative examples of decorin interactions with various growth factors and their receptors and subsequent signalling pathways. The Figure is published with permission of the copyright holder (Kanehisa et al., 2017). Decorin has one GAG side chain which can be either chondroitin sulfate (CS) or dermatan sulfate (DS), and both of these possibilities are presented in the figure. Additional abbreviations used in the figure are as follows: AP4, activating enhancer binding protein 4; Casp3, caspase 3; c‐Cbl, E3 ubiquitin‐protein ligase; elF4B; eukaryotic translation initiation factor 4B; HIF 1α, hypoxia‐inducible factor 1‐α; miR‐21, micro‐RNA 21; mTOR, mechanistic target of rapamycin; Myc, Myc proto‐oncogene protein; PDCD4, programmed cell death 4; PDK‐1, pyruvate dehydrogenase kinase 1; S6, S6 kinase; THBS1, thrombospondin 1; TIMP3, tissue inhibitor of metalloproteinase 3.