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

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.

γ‐Secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells

“…Although the notch transcriptional target HEY1 was downregulated by GSI treatment in our cell models, we cannot exclude that additional targets of GSI were regulated in our study. For example, cell surface receptors of the syndecan family, which act as regulators of invasive growth in endometriosis, have been shown to be sensitive to GSIs . Additional caveats are associated with a potential clinical application of GSIs in an endometriosis setting.…”

“…For example, cell surface receptors of the syndecan family, which act as regulators of invasive growth in endometriosis, 3,33 have been shown to be sensitive to GSIs. 34 Additional caveats are associated with a potential clinical application of GSIs in an endometriosis setting. These include possible fertility-related side effects linked to a downregulation of LIFR, a possible angiogenesis-promoting effect of some GSIs, 11 and gastrointestinal side effects previously reported in clinical trials on GSIs.…”

Dominant Suppression of β1 Integrin by Ectopic CD98-ICD Inhibits Hepatocellular Carcinoma Progression

“…This is another study, to some extent, underlines the inhibitory role of CD98 activity. Moreover, syndecan-1 cCTF (cytoplasmic C-terminal fragment) antagonizes syndecan-1 dependent tumor cell migration by competing with the full length syndecan-1 for intracellular interaction partners and thereby reduces signaling of syndecan-1 [33]. There may be some mechanisms, from the perspective of single molecules, for maintaining cellular homeostasis.…”

Soluble syndecans: biomarkers for diseases and therapeutic options

“…The C‐terminal Sdc1 fragment suppressed tumour cell migration and increased basal phosphorylation of Src and FAK. The authors explain the observed effects with an antagonizing mechanism of the C‐terminal fragment for the Sdc1‐dependent tumour cell migration in vitro and in vivo by dysregulating pro‐adhesive signalling pathways (Pasqualon et al ., ).…”