In the present study, we have investigated the effect of (i) ET-1 (endothelin-1) and its precursor, big ET-1, on MMP (matrix metalloproteinase)-2 and MMP-9 synthesis and activity in osteosarcoma tissue, and (ii) ET-1 receptor antagonists on cell invasion. Using Western blotting, zymography, RT-PCR (reverse transcription–PCR), immunohistochemistry, immunofluorescence and Northern blotting, we have shown that ET-1 and ET-1 receptors (ETA and ETB) were expressed in these cells. Additionally, we have demonstrated that ET-1 markedly induced the synthesis and activity of MMP-2, which was significantly increased when compared with MMP-9. Furthermore, inhibition of NF-κB (nuclear factor κB) activation blocked MMP-2 production and activity, indicating the involvement of NF-κB, a ubiquitous transcription factor playing a central role in the differentiation, proliferation and malignant transformation. Since ET-1 acts as an autocrine mediator through gelatinase induction and because inhibition of ETA receptor is beneficial for reducing both basal and ET-1-induced osteosarcoma cell invasion, targeting this receptor could be an attractive therapeutic alternative for the successful treatment of osteosarcoma.
Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-κB in human osteosarcoma
Mélanie Felx, Marie-Claude Guyot, Marc Isler, Robert E. Turcotte, Josée Doyon, Abdel-Majid Khatib, Séverine Leclerc, Alain Moreau, Florina Moldovan; Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-κB in human osteosarcoma. Clin Sci (Lond) 1 June 2006; 110 (6): 645–654. doi: https://doi.org/10.1042/CS20050286
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