RNA interference as a potential utility for prostate cancer therapy
Dr Badar A Usmani & Prof Anthony J Turner, School of Biochemistry and Microbiology, University of Leeds

Dr Usmani and the team at the University of Leeds

Prostate Cancer (PC) cells can survive androgen withdrawal therapy by utilising alternative growth signals from a range of mitogenic peptides. Cell surface metallopeptidases (eg NEP, EDE , SEP, PHEX) regulate peptide levels. Highly metastatic PC cell lines have low NEP (neutral endopeptidase), but in contrast, high ECE (endothelin-converting enzyme), PHEX and SEP levels. There is also heigh ECE in stroma surrounding prostate adenocarcinomas. The balance of NEP and ECE expression in stromal-epithelial compartments can strongly influence invasion of PC cells. These data emphasize the need to determine the effect of diminishing expression of metallopeptidases at the cell surface. RNA interference (RNAi) will reduce gene expression of specific metallopeptidases and assess the subsequent impact on PC invasion using a 3D invasion model developed at York by the Maitland Group. The outcome of these studies will identify the role of metallopeptidases in invasion and metastases and their potential as therapeutic targets.

The specific aims are:

1. To evaluate the efficacy of a range of siRNA duplexes targeted against NEP, ECE-1, SEP and PHEX in PC cell lines. Real time PCR will confirm degradation of mRNA and efficiency of siRNA molecule. The most efficient siRNA duplex in each case will be identified and used in subsequent experiments.
2. To determine the efficacy of siRNA intervention against specific target molecules of the NEP family in influencing invasive behaviour sing stromal/epithelial co-culture

Project commenced
October 2005

Length of project
1 year

Amount Supported
£38,000