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CANCER

Expression and Localization of Endothelin-Converting Enzyme-1 in Human Prostate Cancer

Louise A. Dawson^*,1, Norman J. Maitland, Paul Berry, Anthony J. Turner^* and Badar A. Usmani^*

^* Proteolysis Research Group, School of Biochemistry & Microbiology, University of Leeds, Leeds LS2 9JT; and YCR Cancer Research Unit, Department of Biology, University of York YO10 5YW, United Kingdom

To whom requests for reprints should be addressed at ¹ School of Biochemistry & Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. E-mail: bmblad{at}bmb.leeds.ac.uk

Abstract

Endothelin (ET)-1 can influence cancer invasion and metastasis by exerting an autocrine (epithelial) or paracrine (stromal) influence on growth. ET-1 is generated from big ET-1 by endothelin-converting enzyme (ECE)-1, which has four recognized isoforms, ECE-1a, ECE-1b, ECE-1c, and ECE-1d, differing only in their amino-terminal regions. This study investigated the expression and localization of the ECE-1 isoforms in prostate cancer (PC). The epithelial cell lines used were androgen-sensitive LNCaP, androgen-independent PC-3 and Du145, and nonmalignant transformed PNT1-a, PNT2-C2, and P4E6 prostate cells. Primary cells derived from malignant and benign tissue from radical prostatectomies were also exploited. Previously, we reported increased ECE-1 expression in androgen-independent PC cell lines, as compared with androgen-sensitive cells. Our present data show that transcripts for all ECE-1 isoforms were present in all epithelial cell lines analyzed. However, only the ECE-1c protein was detectable in PC-3, Du145, PNT2-C2, and PNT1-a cells. ECE-1c localized to both the cell surface and intracellular compartments in individual cell lines. In primary stromal cells, all individual ECE-1 isoforms were expressed at the mRNA level, with the exception of ECE-1a. ECE-1b and ECE-1c protein levels were higher in malignant stromal cells, as compared with benign cells. In stroma, ECE-1c protein was localized to the cell surface, with filamentous immunoreactivity throughout the cell, whereas ECE-1b immunoreactivity was punctate throughout the cytoplasm. The upregulation of the ECE-1c isoform in PC cell lines is being investigated further.

Key Words: endothelin-converting enzyme (ECE) • isoforms • prostate cancer • stromal-epithelial interactions • metallopeptidases • endothelin