Abstract
Simple SummaryOsteosarcoma (OS) is an aggressive, primary bone cancer. OS cells produce altered osteoid whose components participate in signaling correlated to the development of this cancer. Biglycan (BGN), a proteoglycan, is correlated to aggressive OS type and resistance to chemotherapy. A constitutive signaling of insulin-like growth factor receptor I (IGF-IR) signaling in sarcoma progression was established. We showed that biglycan binds IGF-IR resulting in prolonged IGF-IR activation, nuclear translocation, and growth response of the poorly-differentiated MG63 cells correlated to increased aggressiveness markers expression and enhanced chemoresistance. This mechanism is not valid in moderately and well-differentiated, biglycan non-expressing U-2OS and Saos-2 OS cells.Osteosarcoma (OS) is a mesenchymally derived, aggressive bone cancer. OS cells produce an aberrant nonmineralized or partly mineralized extracellular matrix (ECM) whose components participate in signaling pathways connected to specific pathogenic phenotypes of this bone cancer. The expression of biglycan (BGN), a secreted small leucine-rich proteoglycan (SLRP), is correlated to aggressive OS phenotype and resistance to chemotherapy. A constitutive signaling of IGF-IR signaling input in sarcoma progression has been established. Here, we show that biglycan activates the IGF-IR signaling pathway to promote MG63 biglycan-secreting OS cell growth by forming a complex with the receptor. Computational models of IGF-IR and biglycan docking suggest that biglycan binds IGF-IR dimer via its concave surface. Our binding free energy calculations indicate the formation of a stable complex. Biglycan binding results in prolonged IGF-IR activation leading to protracted IGF-IR-dependent cell growth response of the poorly-differentiated MG63 cells. Moreover, biglycan facilitates the internalization (p ≤ 0.01, p ≤ 0.001) and sumoylation-enhanced nuclear translocation of IGF-IR (p ≤ 0.05) and its DNA binding in MG63 cells (p ≤ 0.001). The tyrosine kinase activity of the receptor mediates this mechanism. Furthermore, biglycan downregulates the expression of the tumor-suppressor gene, PTEN (p ≤ 0.01), and increases the expression of endothelial–mesenchymal transition (EMT) and aggressiveness markers vimentin (p ≤ 0.01) and fibronectin (p ≤ 0.01) in MG63 cells. Interestingly, this mechanism is not valid in moderately and well-differentiated, biglycan non-expressing U-2OS and Saos-2 OS cells. Furthermore, biglycan exhibits protective effects against the chemotherapeutic drug, doxorubicin, in MG63 OS cells (p ≤ 0.01). In conclusion, these data indicate a potential direct and adjunct therapeutical role of biglycan in osteosarcoma.
Highlights
Osteosarcoma (OS), a highly malignant neoplasm, is the most common primary tumor of the bone
We have previously shown that biglycan positively modulates poorly differentiated and biglycan-expressing MG63 osteosarcoma cell growth through an IGF-insulin receptor (IR)/βcatenin/ERK1/2 signaling conduit [30]
Considering the previously shown IGF-IR and biglycan co-operation in the regulation of MG63 cell growth, we examined their cellular localization
Summary
Osteosarcoma (OS), a highly malignant neoplasm, is the most common primary tumor of the bone. Bone cells typically form osteoid, a highly specialized organic mineralized extracellular matrix (ECM) mainly consisting of type I collagen, glycoproteins, and proteoglycans (PGs). The small leucine-rich proteoglycans (SLRPs) are a distinct family of PGs with unique characteristics They consist of a small protein core (36–42 kDa) with several leucine-rich repeats (LRRs) and are substituted with a various number of GAG chains [7,8]. Their classification into five distinct classes is based on the conservation of the amino acid residues of the protein core, the organization of disulfide bonds at the N- and C-terminal regions, and their gene homology [9]. An important example is that SLRP interaction with growth factors, and their respective tyrosine kinase receptors, regulates key downstream intracellular signaling pathways [12–14]
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