Endometase in Androgen-Repressed Human Prostate Cancer
Final rept. 25 Feb 2002-25 Feb 2006
FLORIDA STATE UNIV TALLAHASSEE
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This project investigated a biomedical problem related to human prostate cancer invasion and a possible biomarker for cancer diagnosis. We reported the identification and characterization of human matrix metalloproteinase-26 MMP- 26endometasematrilysin-2. We have tested three specific hypotheses 1 The expression levels of MMP-26 is correlated with the metastatic potentials and the degrees of malignancy of human prostate cells 2MMP-26 has unique structure and enzymatic function 3 MMP-26 enhances prostate cancer invasion by digesting extracellular matrix proteins and inactivating serine proteinase inhibitors, and specific inhibitors of MMP-26 block prostate cancer invasion. We report that levels of MMP-26 protein in human prostate carcinomas and high-grade prostate intraepithelial neoplasia from multiple patients were significantly higher than those in prostatitis, benign prostate hyperplasia, and normal prostate glandular tissues. Prostate cancer cells transfected with MMP-26 gene are more invasive and with an inactive mutant are less invasive than the parental cell lines. MMP-26 promoted prostate cancer invasion via activation of pro-gelatinase Bpro-MMP-9. Biochemical studies indicated that endometase active site has an intermediate S1 pocket. Multiple novel synthetic MMP inhibitors are designed, synthesized, and characterized, and they are able to block the invasion of prostate cancer cells. Sixteen papers are attached as part of this final report.
- Anatomy and Physiology
- Medicine and Medical Research