ECE-1 influences prostate cancer cell invasion via ET-1-mediated FAK phosphorylation and ET-1-independent mechanisms.
Plasma concentrations of the mitogenic peptide endothelin-1 (ET-1) are significantly elevated in men with metastatic prostate cancer (PC). ET-1 also contributes to the transition of hormonally regulated androgen-dependent PC to androgen-independent disease. ET-1 is generated from big-ET-1 by endothelin-converting enzyme (ECE-1). ECE-1 is present in PC cell lines and primary tissue and is elevated in primary malignant stromal cells compared with benign. siRNA or shRNA-mediated knockdown of endogenous ECE-1 in either the epithelial or stromal compartment significantly reduced PC cell (PC-3) invasion and migration. The re-addition of ET-1 only partially recovered the effect, suggesting ET-1-dependent and -independent functions for ECE-1 in pPC. The ET-1-independent effect of ECE-1 on PC invasion may be due to modulation of downstream signalling events. Addition of an ECE-1 specific inhibitor to PC-3 cells reduced phosphorylation of focal adhesion kinase (FAK), a signalling molecule known to play a role in PC. siRNA-mediated knockdown of ECE-1 resulted in a significant reduction in FAK phosphorylation. Accordingly, transient ECE-1 overexpression in PNT1-a cells increased FAK phosphorylation. In conclusion, ECE-1 influences PC cell invasion via both ET-1-mediated FAK phosphorylation and ET-1 independent mechanisms.
Whyteside
A R
AR
Institute of Molecular and Cellular Biology, University of Leeds, Faculty of Biological Sciences, Leeds LS2 9JT, UK. a.r.whyteside@leeds.ac.uk
Hinsley
E E
EE
Lambert
L A
LA
McDermott
P J
PJ
Turner
A J
AJ
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D015260:Neprilysin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection
D019332:Endothelin-1; D007527:Isoenzymes; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes