title: Isoforms of endothelin-converting enzyme-1 (ECE-1) have opposing effects on prostate cancer cell invasion.
abstract: Cross-talk between tumour and stromal cells can profoundly influence cancer cell invasion by increasing the availability of mitogenic peptides such as endothelin-1 (ET-1). Endothelin-1 is elevated in men with metastatic prostate cancer (PC), and can exert both an autocrine (epithelial) and a paracrine (stromal) influence on growth. Endothelin-1 is generated from its inactive precursor big-ET-1 by endothelin-converting enzyme 1 (ECE-1). We and others have demonstrated that ECE-1 expression is significantly elevated in tumours and surrounding stromal tissue. Our current data show siRNA-mediated knockdown of stromal ECE-1 reduces epithelial (PC-3) cell invasion in coculture. Interestingly, readdition of ET-1 only partially recovers this effect suggesting a novel role for ECE-1 independent of ET-1 activation. Parallel knockdown of ECE-1 in both stromal and epithelial compartments results in an additive decrease in cell invasion. We extrapolated this observation to the four recognised isoforms ECE-1a, ECE-1b, ECE-1c and ECE-1d. Only ECE-1a and ECE-1c were significant but with reciprocal effects on cell invasion. Transient ECE-1c overexpression increased PC-3 invasiveness through matrigel, whereas transient ECE-1a expression suppressed invasion. Furthermore, transient ECE-1a expression in stromal cells strongly counteracts the effect of transient ECE-1c expression in PC-3 cells. The ECE-1 isoforms may, therefore, be relevant targets for antiinvasive therapy in prostate and other cancers.
authors.affiliation: Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. bmblad@bmb.leeds.ac.uk
authors.forename: L A
authors.initials: LA
authors.lastname: Lambert
authors.forename: A R
authors.initials: AR
authors.lastname: Whyteside
authors.forename: A J
authors.initials: AJ
authors.lastname: Turner
authors.forename: B A
authors.initials: BA
authors.lastname: Usmani
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D034741:RNA, Small Interfering
chemical_list: D017077:Culture Media, Conditioned; D007527:Isoenzymes; D034741:RNA, Small Interfering; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes
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