title: Syndecan-2 overexpression induces osteosarcoma cell apoptosis: Implication of syndecan-2 cytoplasmic domain and JNK signaling.
abstract: Syndecans are cell surface heparan sulfate proteoglycans that serve as co-receptors and modulate the actions of a number of extracellular ligands. Syndecans thereby regulate cell adhesion, proliferation, and differentiation. Studies in cancer cells suggest that syndecans may also modulate cell viability. We previously showed that syndecan-2 controls the growth of normal human osteoblastic cells. In this study, we examined the role of syndecan-2 in osteosarcoma cell proliferation and apoptosis. To this goal, MG63 osteosarcoma cells which express low syndecan-2 levels were transfected to overexpress full-length syndecan-2 or truncated syndecan-2 lacking its cytoplasmic domain. Determination of cell growth by cell counting and 3H-thymidine incorporation showed that truncated syndecan-2 inhibited MG63 cell proliferation. Flow cytometry analysis of DNA content and colony forming test revealed that syndecan-2, but not truncated syndecan-2, induced MG63 cell death. We show that characteristic features of apoptosis such as caspase activation, PARP cleavage, cytochrome c release, increased Bax expression, and DNA fragmentation were associated with syndecan-2-induced cell death. We further show that expression of full-length or truncated syndecan-2 induced differential activation of MAPK phosphorylation in MG63 cells. Notably, syndecan-2 but not truncated syndecan-2 overexpression increased JNK phosphorylation. Moreover, SP600125, a specific inhibitor of JNK, suppressed Bax expression induced by syndecan-2 overexpression, indicating that JNK activation mediates syndecan-2-induced apoptosis. The results show that syndecan-2 induces osteoblastic cell apoptosis through the JNK/Bax apoptotic pathway and that the cytoplasmic domain of syndecan-2 is required for this action. This supports a role for syndecan-2 in the regulation of osteosarcoma cell fate and identifies one signaling pathway by which syndecan-2 induces apoptosis in osteosarcoma cells.
authors.affiliation: Laboratory of Osteoblast Biology and Pathology, Unité 606, INSERM, Lariboisière Hospital, Université Paris 7, 2 rue Ambroise Paré, 75475 cedex 10 Paris, France. dominique.modrowski@larib.inserm.fr
authors.forename: Dominique
authors.initials: D
authors.lastname: Modrowski
authors.forename: Armelle
authors.initials: A
authors.lastname: Orosco
authors.forename: Judicaël
authors.initials: J
authors.lastname: Thévenard
authors.forename: Olivia
authors.initials: O
authors.lastname: Fromigué
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001859:Bone Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D012516:Osteosarcoma; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D053669:Syndecan-2
chemical_list: D000873:Anthracenes; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508245:SDC2 protein, human; D053669:Syndecan-2; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases