Mechanisms of cytokine action and inflammation; products of arachidonic and linoleic acid metabolism of the 12-Lipoxygeanse (12-LO) enzymes leading to cellular growth, matrix production, apoptosis and cell migration

The Nadler group studies mechanisms of cytokine action and inflammation with a special emphasis on products of arachidonic and linoleic acid metabolism of the 12/15 Lipoxygenase (LO) enzymes.  These products can lead to cellular growth, matrix production, apoptosis under certain conditions and cell migration.  Many cancer cell types either produce or respond to these products.  In particular, pancreatic tumor cell lines show growth and activation of MAP kinase cascades in response to 12-HETE a specific product of the 12-LO pathway.  In addition colon, breast, melanoma and prostate cancers in particular express these enzymes or respond to lipids generated by the LO enzymes.  The receptor for 12-HETE has not been cloned.  We have begun studies to identify this receptor, which is likely to be G-protein coupled.  Recent work in our group has compared 12-LO expression in aldosterone-producing adenomas (APA) compared to normal adrenal tissue.  We found increased (3-fold) expression of 12-LO protein APA compared to normal adrenals, and even more dramatic increases in two fatty acid metabolites of 12-LO, 12-hydroxyeicosatetraneoic acids (196-fold) and 9-hydroperoxyoctadecadienoic acids (91-fold).  The tumors also expressed 8- to 9-fold higher levels of aldosterone, and this was accompanied by elevated levels of activated p39 MAPK and phosphorylated CREB.  The results suggest that increased 12-LO may play a key role in regulating aldosterone synthesis in these adenomas in part by activating 938 MAPK and CREB activity.  Very recent evidence has shown a direct role of 12/15 LO gene in bone density supporting a very likely role of this gene and its products in bone formation/destruction associated with cancer related bone disease.  This is an unexplored area that has great clinical potential to treat various forms of cancer or related metastasis.