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 (ET(A)R) and endothelin-B receptor (ET(B)R)) 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-i) and siRNA targeting of the ECE-1 gene on SCC cell proliferation. We observed the expression of ET-1, ET(A)R, ET(B)R and all endothelin-converting enzyme-1 (ECE-1) isoforms in oral SCC cells, but only the expression of ET-1, ET(B)R and ECE-1 was increased when compared to normal human epidermal keratinocytes. ET-1 alone stimulated proliferation of oral SCC cells. Antagonists of either ET(A)R or ET(B)R 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.
Awano
Shuji
S
Proteolysis Research Group, School of Biochemistry and Microbiology, University of Leeds, Leeds, United Kingdom. awa-shu@kyu-dent.ac.jp
Dawson
Louise A
LA
Hunter
Alison R
AR
Turner
Anthony J
AJ
Usmani
Badar A
BA
D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000503:physiopathology*; D049109:Cell Proliferation; D019332:Endothelin-1 / Q000032:analysis / Q000096:biosynthesis*; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D009062:Mouth Neoplasms / Q000235:genetics / Q000503:physiopathology*; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D044022:Receptor, Endothelin A / Q000032:analysis / Q000096:biosynthesis*; D044023:Receptor, Endothelin B / Q000032:analysis / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D019332:Endothelin-1; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes