Regulartory Mechanism of Ovarian Aromatase by Nuclear Receptor, PPARγ : RXR

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Our previous studies demonstrated that PPARgamma specific-ligand troglitazone (TGZ) and/or RXR specific ligand LG100268 (LG) decreased the P450 aromatase activity in cultured human ovarian granulosa cells as well as in the human granulose-like tumor KGN cells. At the present study we evidenced that TGZ+LG decreased P45Oarom promoter II in both the ovarian KGN cells and the fibroblast NIH-3T3 cells in a PPARgamma dependent manner. Further, the TGZ+LG inhibition to both aromatase activity and the P450arom promoter II was completely eliminated when NF-kappaB was blocked, suggesting NF-kappaB, which is endogenously expressed in both fibroblast and the granulose cells, might be the mediator of the inhibition. On the other hand, activation of NE-kappaB either by a direct cotransfection of P65 subunit or by transfection of NIK to activate the endogenous NF-kappaB, was found to up-regulate P450arom promoter II activity. Though activation of PPARgamma.RXR could not interfere with endogenous expression of IkappaBalpha nor that of P65, it did impair the transactivation ability of NF-kappaB, as documented by a NF-kappaB elements containing luciferase reporter, which was dose-dependently inhibited by IGZ+LG.Our data reinforce the potential use of synthetic PPARgamma and RXR ligands for diseases like breast cancer where estrogen plays prominent roles. And besides the classical P450aorm modulators like PKA, SF-1, nuclear receptors like PPARgamma, RXR and their cross-talk with NF-kappa B may also have important roles, wherein, PPARgama inhibits P450arom gene through NF-kappaB.