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

SIMPLE SUMMARY: Osteosarcoma (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 cons...

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Autores principales: Giatagana, Eirini-Maria, Berdiaki, Aikaterini, Gaardløs, Margrethe, Samsonov, Sergey A., Tzanakakis, George N., Nikitovic, Dragana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909324/
https://www.ncbi.nlm.nih.gov/pubmed/35267503
http://dx.doi.org/10.3390/cancers14051196
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author Giatagana, Eirini-Maria
Berdiaki, Aikaterini
Gaardløs, Margrethe
Samsonov, Sergey A.
Tzanakakis, George N.
Nikitovic, Dragana
author_facet Giatagana, Eirini-Maria
Berdiaki, Aikaterini
Gaardløs, Margrethe
Samsonov, Sergey A.
Tzanakakis, George N.
Nikitovic, Dragana
author_sort Giatagana, Eirini-Maria
collection PubMed
description SIMPLE SUMMARY: Osteosarcoma (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. 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.
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spelling pubmed-89093242022-03-11 Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy Giatagana, Eirini-Maria Berdiaki, Aikaterini Gaardløs, Margrethe Samsonov, Sergey A. Tzanakakis, George N. Nikitovic, Dragana Cancers (Basel) Article SIMPLE SUMMARY: Osteosarcoma (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. 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. MDPI 2022-02-25 /pmc/articles/PMC8909324/ /pubmed/35267503 http://dx.doi.org/10.3390/cancers14051196 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Giatagana, Eirini-Maria
Berdiaki, Aikaterini
Gaardløs, Margrethe
Samsonov, Sergey A.
Tzanakakis, George N.
Nikitovic, Dragana
Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy
title Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy
title_full Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy
title_fullStr Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy
title_full_unstemmed Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy
title_short Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy
title_sort biglycan interacts with type i insulin-like receptor (igf-ir) signaling pathway to regulate osteosarcoma cell growth and response to chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909324/
https://www.ncbi.nlm.nih.gov/pubmed/35267503
http://dx.doi.org/10.3390/cancers14051196
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