Arachidonate 15-Lipoxygenase 2 as an Endogenous Inhibitor of Prostate Cancer Development.

摘要

Our recent work has demonstrated that: (1) 15-lipoxygenase 2 (15- LOX2), which metabolizes AA to generate 15(S)-HETE, is the major LOX expressed in adult prostate epithelial cells but down-regulated or lost in PCa in vitro as well as in vivo; (2) 15-LOX2 expression is inversely correlated with the pathological grade and Gleason scores of PCapatients; (3) 15-LOX2 is a negative cell-cycle regulator in normal human prostate (NHP) epithelial cells; (4) 15(S)- HETE inhibits PCa cell migration and invasion and re-expression of 15-LOX2, or its splice variant 15-LOX2sv-b,inhibits PCa cell proliferation in vitro and tumor development in vivo; (5) 15-LOX2 expression in NHP cells is positively regulated by the transcription factor Sp1 and negatively regulated by Sp3; (6) The expression of 15- LOX2 and its multiple splice variants in NHP cells is cell-autonomously induced and is correlated with and causally involved in the senescence of NHP cells; (7) Transgenic expression of 15-LOX2, or its splice variant, 15-LOX2sv-b, in mouse prostate induces unique gene expression profile and causes degenerative prostate overgrowth; and 8) Finally, 15-LOX2 transgene expression inhibits TRAMP tumor development in the compound mice. These observations togetogether support initial hypothesis that 15-LOX2 represents a functional prostate tumor suppressor, whose loss of expression contributes to PCa development. We initially proposed two Specific Aims: 1) to test the hypothesis that15-LOX2 inhibits PCa development in an orthotopic implantation model using an inducible 15-LOX2 exprexpression systemd 2) to test the hypothesis that 15-LOX2 inhibits PCa development in newly developed prosprostate specific transgenicmal models. We have now accomplished both Specific Aims (see detailed Progress Report).