Glycosaminoglycans and syndecan-4 are involved in SDF-1/CXCL12-mediated invasion of human epitheloid carcinoma HeLa cells

• Published in: Biochimica et biophysica acta Vol. 1790; no. 12; pp. 1643 - 1650
• Main Authors: Brule, Severine, Friand, Véronique, Sutton, Angela, Baleux, Françoise, Gattegno, Liliane, Charnaux, Nathalie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2009; Elsevier
• Subjects: Anthracenes - pharmacology; Biochemistry, Molecular Biology; Carcinoma in Situ - metabolism; Carcinoma in Situ - pathology; Cell Movement - drug effects; Chemokine; Chemokine CXCL12 - antagonists & inhibitors; Chemokine CXCL12 - pharmacology; Chemokine CXCL12 - physiology; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Female; Glycosaminoglycan; Glycosaminoglycans - physiology; HeLa Cells; Heterocyclic Compounds - pharmacology; Humans; Invasion; Life Sciences; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase 9 - physiology; Neoplasm Invasiveness; Proteoglycan; SDF-1/CXCL12; Signal Transduction - drug effects; Syndecan; Syndecan-4 - physiology; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Chemokine; Proteoglycan; Glycosaminoglycan; SDF-1/CXCL12; Invasion; Syndecan
• ISSN: 0304-4165; 0006-3002; 0167-4889; 1872-8006
• DOI: 10.1016/j.bbagen.2009.08.001

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). 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. The SDF-1/CXCL12-induced cell invasion is dependent on CXCR4. Furthermore, Protein Kinase C delta (PKC δ) 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 β- 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. These data suggest that targeting the glycosaminoglycan/chemokine interaction could be a new therapeutic approach for carcinomas in which SDF-1/CXCL12 is involved.