Novel Fatty Acid Lipoxygenases in the Development of Human and Murine Prostate Cancer
Abstract
Identification of novel genes selectively expressed in the prostate and altered in prostate carcinoma may lead to novel therapies or prognostic markers in prostate cancer (Pca). We have utilized a combination of immunohistochemistry, enzyme activity assays, and mRNA analyses to demonstrate that the novel lipoxygenase 1 5-lipoxygenase-2 (1 5-LOX-2) is expressed in differentiated secretory cells of benign prostate and reduced in the majority of Pcas. We have demonstrated that the nuclear transcription factor peroxisome proliferator activated receptor gamma (PPAR gamma) is present in benign and malignant prostate and Pca cell lines and that the enzymatic product of 1 5-LOX-2, 1 5-hydroxyeicosatetraenoic acid (1 5-HETE), activates PPAR gamma and inhibits proliferation of Pca cell lines. Transgenic mouse models of Pca created with the long probasin promoter (LPB) and the SV40 large T-antigen (Tag) progress from precursor lesions to invasive and metastatic carcinoma. Although we have demonstrated that the murine homologue of 1 5-LOX-2, an 8-LOX, is not expressed in the wild type or LPB-Tag prostate, we have observed other alterations in arachidonic acid metabolizing enzymes that have been reported in human Pca. These mouse models may provide useful information regarding the role of these pathways in Pca development and progression. Our data in human Pca indicates that 1 5-LOX-2 derived 1 5-HETE may constitute an endogenous ligand for PPAR gamma in human prostate. That 1 5-LOX-2 is reduced in Pca supports utilization of PPAR gamma -agonists in the treatment of Pca.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2000
- Accession Number
- ADB268113
Entities
People
- Scott Shappell
Organizations
- Vanderbilt University