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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.
AuthorsDominique Modrowski, Armelle Orosco, Judicaël Thévenard, Olivia Fromigué, Pierre J Marie
JournalBone (Bone) Vol. 37 Issue 2 Pg. 180-9 (Aug 2005) ISSN: 8756-3282 [Print] United States
PMID15936998 (Publication Type: Journal Article)
Chemical References
  • Anthracenes
  • Membrane Glycoproteins
  • Proteoglycans
  • SDC2 protein, human
  • Syndecan-2
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
Topics
  • Anthracenes (pharmacology)
  • Apoptosis (physiology)
  • Bone Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival (physiology)
  • Humans
  • JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, physiology)
  • MAP Kinase Signaling System (physiology)
  • Membrane Glycoproteins (biosynthesis, genetics)
  • Mutation
  • Osteoblasts (cytology, metabolism)
  • Osteosarcoma
  • Phosphorylation
  • Protein Structure, Tertiary
  • Proteoglycans (biosynthesis, genetics)
  • Signal Transduction
  • Syndecan-2

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