Dietary fats are known to influence the incidence and progression of prostate cancer. 15-lipoxygenase-2(15-LOX-2) is a fatty acid metabolizing enzymes catalyzing the formation of 15(S)-hydroxyeicosatetraenoid acid (HETE) using arachidonic acid as the substrate. 15-LOX-2 is expressed in normal prostate epithelium but its expression and activity are frequently lost in prostate carcinoma. To study the role of 15-LOX-2 in prostate cancer, we restored the expression of 15-LOX-2 as a fusion protein with GFP in prostate carcinoma cells (DU145 and PC-3 cells). When restored in hormone-independent PC-3 or DU145 cells, 15-LOX-2 did not abrogate the tumorigenicity of PC-3 or DU145 cells in animal models. But, the tumors with 15-LOX-2 expression restored were dormant. They grew significantly slower than those derived from vector controls. The data suggest that 15-LOX-2 sustains tumor dormancy while having no effects on tumor formation. Interestingly, the expression of vascular endothelial growth factor A (VEGF-A or VEGF) was drastically reduced in prostate cancer cells with 15-LOX-2 expression restored. Further, VEGF promoter activities were reduced in prostate carcinoma cells with 15-LOX-2 expression restored. Using a series of VEGF promoter deletion constructs, a region between the -88 and -66 of VEGF promoter was identified as critical for 15-LOX-2 to suppress VEGF gene expression. Our studies suggest that 15-LOX-2 induces tumor dormancy by suppressing VEGF gene expression in prostate cancer, and that loss of 15-LOX-2 represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]