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Oncotarget. 2015 Oct 13;6(31):31295-312. doi: 10.18632/oncotarget.5174.

A cytoplasmic C-terminal fragment of Syndecan-1 is generated by sequential proteolysis and antagonizes Syndecan-1 dependent lung tumor cell migration.

Author information

1
Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
2
Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
3
Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany.
4
Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany.
5
Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany.

Abstract

Syndecan-1 is a surface expressed heparan sulphate proteoglycan, which is upregulated by several tumor types and involved in tumor cell migration and metastasis. Syndecan-1 is shed from the cell surface and the remaining transmembrane fragment undergoes intramembrane proteolysis by γ-secretase. We here show that this generates a cytoplasmic C-terminal fragment (cCTF). In epithelial lung tumor A549 cells the endogenously produced cCTF accumulated when its proteasomal degradation was blocked with bortezomib and this accumulation was prevented by γ-secretase inhibition. Overexpression of the cCTF suppressed migration and invasion of A549 cells. This inhibitory effect was only seen when endogenous Syndecan-1 was present, but not in Syndecan-1 deficient cells. Further, overexpression of Syndecan-1 cCTF increased the basal activation of Src kinase, focal adhesion kinase (FAK) and Rho GTPase. This was associated with increased adhesion to fibronectin and collagen G and an increased recruitment of paxillin to focal adhesions. Moreover, lung tumor formation of A549 cells in mice was reduced by overexpression of Syndecan-1 cCTF. Finally, delivery of a synthetic peptide corresponding to the Syndecan-1 cCTF suppressed A549 cell migration and increased basal phosphorylation of Src and FAK. Our data indicate that the Syndecan-1 cCTF antagonizes Syndecan-1 dependent tumor cell migration in vitro and in vivo by dysregulating proadhesive signaling pathways and suggest that the cCTF can be used as an inhibitory peptide.

KEYWORDS:

adhesion; lung cancer; migration; proteoglycan; proteolysis

PMID:
26378057
PMCID:
PMC4741606
DOI:
10.18632/oncotarget.5174
[Indexed for MEDLINE]
Free PMC Article

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