Glycosaminoglycans and syndecan-4 are involved in SDF-1/CXCL12-mediated invasion of human epitheloid carcinoma HeLa cells.
BACKGROUND
In addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. The CXC-chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 mediates its biological activities through activation of G protein-coupled receptor CXCR4 and binds to glycosaminoglycans (GAGs).


METHODS
Using Bio-coat cell migration chambers, specific antagonists, flow cytometry and RNA interference, we evaluate the involvement of heparan sulfate proteoglycans (HSPG) in the SDF-1/CXCL12-induced invasion of human cervix epitheloid carcinoma HeLa cells.


RESULTS
The SDF-1/CXCL12-induced cell invasion is dependent on CXCR4. Furthermore, Protein Kinase C delta (PKC delta) and c-jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) are implicated in this event, but not extracellular signal-regulated kinase (ERK) 1/2. Moreover, the invasion of HeLa cells induced by SDF-1/CXCL12 was dependent on matrix metalloproteinase-9 (MMP-9). The pre-incubation of HeLa cells with heparin or with anti-heparan sulfate antibodies or with beta-d-xyloside inhibited SDF-1/CXCL12-mediated cell invasion. Furthermore, the down-regulation of syndecan-4, a heparan sulfate proteoglycan, decreased SDF-1/CXCL12-mediated HeLa cell invasion. GAGs, probably on syndecan-4, are involved in SDF-1/CXCL12-mediated cell chemotaxis.


CONCLUSIONS
These data suggest that targeting the glycosaminoglycan/chemokine interaction could be a new therapeutic approach for carcinomas in which SDF-1/CXCL12 is involved.
Brule
Severine
S
INSERM U698, Université Paris 13, Bobigny, France. severinebrule@yahoo.fr
Friand
Véronique
V
Sutton
Angela
A
Baleux
Françoise
F
Gattegno
Liliane
L
Charnaux
Nathalie
N
D000873:Anthracenes / Q000494:pharmacology; D001596:Benzylamines; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D000080027:Cyclams; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006025:Glycosaminoglycans / Q000502:physiology*; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000187:drug effects; D053671:Syndecan-4 / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
D000873:Anthracenes; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D004791:Enzyme Inhibitors; D006025:Glycosaminoglycans; D006571:Heterocyclic Compounds; C508304:SDC4 protein, human; D053671:Syndecan-4; C432165:pyrazolanthrone; D020780:Matrix Metalloproteinase 9; C088327:plerixafor