Orthotopic expression of human 15-lipoxygenase (LO)-1 in the dorsolateral prostate of normal wild-type C57BL/6 mouse causes PIN-like lesions

• Published in: Prostaglandins & other lipid mediators 2006-10, Vol.81 (1), p.1-13
• Main Authors: Sen, Malabika, McHugh, Kevin, Hutzley, Justin, Philips, Brian J., Dhir, Rajiv, Parwani, Anil V., Kelavkar, Uddhav P.
• Format: Article
• Language: English
• Subjects: 13- S-Hydroxyoctadecadienoic acid (13- S-HODE); 15-Lipoxygenase-1 (15-LO-1); Adenoviridae - genetics; Adenoviridae - metabolism; Animals; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Biomarkers - metabolism; C57BL/6 mouse; Cell Line; Fibroblast growth factor (FGF); Humans; Isoenzymes - genetics; Isoenzymes - metabolism; Ki-67 Antigen - metabolism; Linoleic acid (LA); Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Prostate - anatomy & histology; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2006.05.024

The lipid-peroxidating enzyme, 15-lipoxygenase (LO)-1 and its metabolite, 13- S-hydroxyoctadecadienoic acid (13- S-HODE), likely contribute to prostate tumorigenesis. Thus, this study evaluated adenovirus-mediated overexpression of 15-LO-1 on normal mouse prostate. Adenovirus expressing either human 15-LO-1 tagged with green fluorescent protein (GFP) or GFP alone was orthotopically injected into the dorsolateral prostates of C57BL/6 mice, three times over the course of 60 days. On day 90, pathological changes in prostate tissue were assessed by hematoxylin and eosin (H&E) staining. Expression of the proliferation marker Ki-67 was evaluated by immunohistochemistry and expression of angiogenesis markers were analyzed by an antibody array. Based on the latter study, immunoprecipitation analysis was used to measure the effect of 13- S-HODE, with or without conditioned media, on fibroblast growth factor-a and b (FGF-a and FGF-b) expression in human PrEC (normal prostate epithelial), PrSMC (normal prostate smooth muscle) and PrSC (normal prostate stromal) lines. Expression of viral 15-LO-1-GFP, but not GFP alone, resulted in the development of a prostate intraepithelial neoplasia (PIN)-like phenotype with increased expression of Ki-67. Aberrant 15-LO-1 expression also induced the angiogenic markers FGF-a and FGF-b. Human PrEC, PrSMC and PrSC lines demonstrated an increase in FGF-b expression upon stimulation with 13- S-HODE, which was further increased by the addition of conditioned media from the epithelial or smooth muscle cells. Using adenoviral mediated 15-LO-1 gene delivery, this study suggests that aberrant 15-LO-1 overexpression in normal prostate can trigger events leading to prostate epithelial and stromal cell proliferation. Thus, our findings demonstrate the effectiveness of this viral system for 15-LO-1 expression studies in tissues.