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022P University of Cambridge
The Twelfth International Conference on Endothelin 2011



Molecular mechanisms regulating ECE-1 expression in prostate cancer

Alison Whyteside1, Anthony Turner1, Daniel Lambert2. 1University of Leeds, LS2 9JT, United Kingdom, 2University of Sheffield, S10 2TA, United Kingdom.


It is widely known that the mitogenic peptide endothelin-1 (ET-1) influences cancer invasion and metastasis. Plasma ET-1 levels are significantly elevated in men with metastatic prostate cancer (PC). ET-1 is also involved in the transition of hormonally regulated androgen-dependent disease to androgen-independent PC. ET-1 is produced from big ET-1 by endothelin-converting enzyme-1 (ECE-1), expression of which is upregulated in prostate cancer. In this study we examined the aberrant molecular regulation of ECE-1 expression in prostate cancer, focussing particularly on post-transcriptional regulation. We first utilised a reporter assay in which the 3’ untranslated region (UTR), a region of the transcript commonly involved in post-transcriptional regulation, of ECE-1 was fused to the luciferase coding sequence and transfected into PC-3 prostate cancer cells. The full-length 3’ UTR significantly decreased luciferase activity by 85% compared to empty vector. Whilst this decrease was greatest in PC-3 cells, it was also seen in normal prostate cells (RWPE1) and non-prostate cells (Huh7). We subsequently identified six ECE-1 transcripts with truncated 3’ UTRs in PC-3 cells by 3’RACE analysis. The truncated UTRs generated greater luciferase activity than the full length UTR when utilised in a reporter assay. Furthermore, addition of the full length UTR to the ECE-1 coding region markedly suppressed ECE-1 protein expression when heterologously expressed in PC and non-PC cells suggesting that UTR truncation, a common feature of malignant cells, may result in increased ECE-1 expression in PC. Studies are ongoing to assess the role of factors which may interact with the ECE-1 3’UTR, such as microRNA, in the findings presented here. The identification of a key role for the 3’UTR in the regulation of ECE-1 expression may prove useful in the development of novel therapeutic strategies targeting the endothelin axis in prostate cancer. This work is supported by Yorkshire Cancer Research.