Members of the serine protease (SP) gene family carry out diverse functional roles in normal mammalian physiology and also contribute significantly to the pathogenesis of disease. Several members of the SP gene family are of relevance for the study of prostate carcinogenesis. Two of these, prostate specific antigen (PSA) and human glandular kallikrein 2 (hK2) exhibit an expression profile essentially restricted to the human prostate. Exploiting the tissue compartmentalization of PSA has revolutionized the management of patients with prostate cancer by providing a tool for the early diagnosis and subsequent monitoring of patients with prostate cancer. There is emerging evidence that these prostate serine protease play a direct physiological role in the pathogenesis of metastatic prostate cancer, and further that these serine proteases can be used as targets for a variety of therapeutic strategies including the targeting of specific cytotoxic compounds to prostate tumor cells and as reagents for gene-therapy based approaches. They have recently identified two serine proteases, prostase and TMPRSS2, that exhibit a tissue expression pattern with high prostate specificity. This proposal is based on the hypothesis that: Progression to invasive and metastatic prostate cancer is driven by the increased or ectopic expression of specific serine protease enzyme expressed in prostate cancer cells. These serine proteases influence metastatic disease through protease action on barriers to invasion (e.g. extracellular matrix) and growth factor systems (e.g. IGF). This proposal will test this hypothesis by accomplishing the following Specific Aims: 1) Characterize the regulation of prostate and TMPRSS2 serine protease gene expression. 2) Identify activators and substrates of the prostase and TMPRSS2 proteins. 3) Develop polyclonal and monoclonal anti-prostase and anti-TMPRSS2 antibodies for the evaluation of protein expression in tissues representing a range of normal, benign, and malignant prostate pathology. 4) Characterize the role of prostate and TMPRSS2 in prostate cancer bone metastasis using in vitro and in vivo systems.
| Nelson, Peter S; Clegg, Nigel; Arnold, Hugh et al. (2002) The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci U S A 99:11890-5 |
| Takayama, T K; McMullen, B A; Nelson, P S et al. (2001) Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase. Biochemistry 40:15341-8 |
