Endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE-1 blocks cell proliferation

The present study focused on the endothelin axis in human oral squamous cell carcinoma (SCC) cells. We investigated the expression and distribution of endothelin-1 (ET-1), its receptors (endothelin-A receptor (ETAR) and endothelin-B receptor (ETBR)) and isoforms of its specific converting enzyme (ECE-1a, 1b, 1c) and the report on their relative influences on cell proliferation. We also investigated the effect of an ECE-specific inhibitor (ECE-1) and siRNA targeting of the ECE-1 gene on SCC cell proliferation. We observed the expression of ET-1, ETAR, ETBR and all endothelin-converting enzyme-1 (ECE-1) isoforms in oral SCC cells, but only the expression of ET-1, ETBR and ECE-1 was increased when compared to normal human epidermal keratinocytes. ET-I alone stimulated proliferation of oral SCC cells. Antagonists of either ETAR or ETBR inhibited ET-1-mediated proliferation. Decreased ECE-1 expression after ECE siRNA treatment reduced SCC cell proliferation. Antiproliferative effects were also observed by inhibiting ECE activity with ECE-i. In conclusion, the present study demonstrates that modulation of the endothelin system in oral SCC cells might provide a novel therapeutic protocol for oral cancer. (c) 2005 Wiley-Liss, Inc.