Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy

Abstract

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.

Comprehensive analysis of potential cellular communication networks in advanced osteosarcoma using single-cell RNA sequencing data

“…The details of all signaling pathway networks identified were also shown in Figures 6A-C (A: numbers of ligand receptors among all cell types; B: weights of ligand receptors among all cell types; C: chordal graph of ligand-receptor interactions among all cell types). Among the total of 57 signaling pathways, the following signaling pathways were related to osteosarcoma: COLLAGEN ( Baumann and Hennet, 2016 ; Elenjord et al, 2009 ; Levinson et al, 2002 ; Yamaguchi et al, 2005 ), CD99 ( Manara et al, 2006 ; Sciandra et al, 2014 ; Zucchini et al, 2014 ), PTN ( He et al, 2019 ; Qin et al, 2022 ; Sun et al, 2020 ), MIF( Liu et al, 2014 ), SPP1( Dalla-Torre et al, 2006 ; Li et al, 2017 ), FN1( Saba et al, 2019 ; Zhou et al, 2019 ), LAMININ( Heino and Massague, 1989 ), FGF ( Kurogi et al, 1996 ; Laulederkind et al, 2000 ; Li et al, 2019 ; Xu et al, 2010 ), VEGF ( Ji et al, 2020 ; Lei et al, 2018 ; Oda et al, 2006 ; Tsai et al, 2017 ; Zhang et al, 2019 ), GALECTIN( Gomez-Brouchet et al, 2010 ; Miao et al, 2014 ; Park et al, 2015 ; Zhou et al, 2014 ), PERIOSTIN( Ma et al, 2020 ; Xu et al, 2022 ), VISFATIN( Cheng et al, 2015 ; Wang et al, 2019 , 2016 ), ITGB2 ( Dai et al, 2018 ), NOTCH( Jin et al, 2017 ; Mu et al, 2013 ; Ongaro et al, 2016 ; Tanaka et al, 2009 ; Zhang et al, 2010 ), IGF ( Armakolas et al, 2016 ; Giatagana et al, 2022 ; Gvozdenovic et al, 2017 ; Molina et al, 2019 ; Tan et al, 2015 ), VWF( Wang et al, 2020 ), and PDGF ( Chen et al, 2009 ; Egners et al, 2018 ; Heldin et al, 1986 ). The ligand-receptor interact...…”

The Landscape of Small Leucine-Rich Proteoglycan Impact on Cancer Pathogenesis with a Focus on Biglycan and Lumican

“…Studies examining the variabilities in the protein core and glycosylation patterns have described 45 different PGs [16]. However, the localization of secreted and cell membrane PGs can be changed due to alterations in synthesis/endocytosis or shedding [25,35]. The expression of PGs, their ECM, and cellular and specific subcellular localization varies between cancer types, thus modulating cell function and tumor differentiation [1,6].…”

“…Finally, as discussed in bone tissue, SLRPs, by binding a plethora of cell membrane receptors, growth factors, and cytokines, can initiate and regulate specific intracellular signaling, thereby modulating cell functions [53]. Notably, a multitude of studies have shown that SLRPs' interaction with tyrosine kinase receptors or growth factors regulates biological functions and tumor progression [23][24][25][26]. In addition, SLRPs can be secreted upon tissue insult, bind toll-like receptors (TLRs), and take on the role of damage-associated molecular patterns [27].…”

“…Notably, GAG chains can modify protein core-ligand interactions by introducing immense variability in their signaling [18][19][20]. A plethora of studies have demonstrated that SLRPs' expression is altered in tumors [21,22] and that by interacting with tyrosine kinase receptors or growth factors, they affect tumor behavior [23][24][25][26]. Moreover, in the case of tissue insult and damage, SLRPs bind toll-like receptors (TLRs) and are released to act as damage-associated molecular patterns [27].…”

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

“…In addition, the small leucine-rich repeat proteoglycan of bone extracellular matrix tissue biglycan, which is correlated with an aggressive phenotype of osteosarcoma, supported tumor growth and induced resistance to chemotherapy drug doxorubicin by forming a complex with IGF-1R leading to activation of the IGF-1R signaling pathway in human osteosarcoma cell line MG63 ( 37 ). Similarly, miR-520b promoted doxorubicin sensitivity in breast cancer cells through downregulation of IGF-1R, i.e., abrogating tumor development, metastasis, and resistance to chemotherapy induced by IGF-1R ( 38 ).…”