Better interventions are needed to prevent the high mortality of prostate cancer cancer (PCa). We have discovered that a lipid-metabolizing enzyme 15-lipoxygenase-1 (15-LO-1) is overexpressed in human PCa, its expression increased with increasing Gleason score grades. This report is paralleled by two main observations: 1. The in vivo studies using the engineered human PCa cell line, PC-3, overexpressing 15-LO-1 that caused aggressive tumors in athymie mice; and, 2. A similar increased expression of its murine homologue, Leukocyte-type 12/15-LO, was seen in a prostate cancer mouse model called LPB-Tag with high-grade prostatic intraepithelial neoplasia (HGPIN) and invasive metastatic carcinoma. These observations strongly suggest a very important and critical role of 15-LO-1 and provide a strong rationale for exploring its role in the progression and metastasis of PCa. To test our hypothesis, we propose as an initial feasibility pilot study to generate a new transgenic mouse called FLiMP in order to express the human 15-LO-1 gene specifically in the epithelium of mouse prostate. The long-term goal of this proposal is to elucidate the biology and molecular mechanisms whereby 15-LO-1 over expression contributes to the initiation and progression of prostate cancer. To this end, two specific aims are proposed: 1) To test the hypothesis that overexpression of 15-LO-1 by the prostate gland facilitates the progression of prostate cancer; and 2) To test the hypothesis that 15-LO-1 specific abrogation inhibits the initiation and/or progression of PCa. To accomplish the first specific aim, the consequence of prostate specific human 15-LO-1 transgene expression will be characterized with respect to time to palpable tumor, tumor grade and metastatic incidence in transgenic mice carrying a CAG (a synthetic promoter using cytomegalovirus (CMV) enhancer and chicken beta-actin promoter for ubiquitous expression)-directed 15-LO-1 transgene in FliMP mice (by crossing the B6-TgN (CAGloxPCAT-STOPLoxPh15LO- 1) E mouse with Probasin-Cre mouse). To accomplish the second specific aim, the efficacy of pharamacologic and molecular biologic inhibition of 15-LO-1 activity will be tested and characterized with respect to time to palpable tumor, tumor grade and metastatic incidence in this mouse model. Therefore, the strategies designed to manipulate prostate-specific gene expression developed in this project will be used both to identify biological factors involved in the progression of prostate cancer and in the development and testing of innovative medical strategies for the prevention and treatment of PCa.
| Kelavkar, Uddhav P; Parwani, Anil V; Shappell, Scott B et al. (2006) Conditional expression of human 15-lipoxygenase-1 in mouse prostate induces prostatic intraepithelial neoplasia: the FLiMP mouse model. Neoplasia 8:510-22 |
| Sen, Malabika; McHugh, Kevin; Hutzley, Justin et al. (2006) Orthotopic expression of human 15-lipoxygenase (LO)-1 in the dorsolateral prostate of normal wild-type C57BL/6 mouse causes PIN-like lesions. Prostaglandins Other Lipid Mediat 81:1-13 |
| Kelavkar, Uddhav P; Cohen, Cynthia (2004) 15-lipoxygenase-1 expression upregulates and activates insulin-like growth factor-1 receptor in prostate cancer cells. Neoplasia 6:41-52 |
| Kelavkar, Uddhav P; Glasgow, Wayne; Olson, Sandra J et al. (2004) Overexpression of 12/15-lipoxygenase, an ortholog of human 15-lipoxygenase-1, in the prostate tumors of TRAMP mice. Neoplasia 6:821-30 |
