15-Lipoxygenase-1 metabolites down-regulate peroxisome proliferator-activated receptor gamma via the MAPK signaling pathway

Human colon tumors have elevated levels of 15-lipoxygenase-1 (15-LO-1), sug gesting that 15-LO-1 may play a role in the development of colorectal cance r. Also, 15-LO-1 metabolites can up-regulate epidermal growth factor signal ing pathways, which results in an increase in mitogenesis. However, metabol ites of 15-LO-1 can serve as ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma), and activation of this receptor causes most co lon cancer cell lines to undergo a differentiative response and reverse the ir malignant phenotype. Hence, the role 15-LO-1 plays in colon cancer is no t clear. To clarify the role of 15-LO-1 in carcinogenesis, the effect of 15 -LO-1 and its metabolites on epidermal growth factor signaling and PPAR gam ma was investigated. In HCT-116 cells, exogenously added 15-LO-1 metabolite s, 13-(S)-hydroxyoctadecadienoic acid, 13-(S)-hydroxyoctadecadienoic acid, and 13-(S)-hydroperoxyoctadecadienoic acid, up-regulated the MAPK signaling pathway, and an increase in PPAR gamma phosphorylation was observed. Furth ermore, in stable overexpressing 15-LO-1 HCT-116 cells, which produce endog enous 15-LO-1 metabolites, an up-regulation in mitogen-activated protein ki nase and PPAR gamma phosphorylation was observed. Incubation with a MAPK in hibitor ablated MAPK and PPAR gamma phosphorylation. The 15-LO-1 up-regulat es MAPK activity and increases PPAR gamma phosphorylation, resulting in a d own-regulation of PPAR gamma activity. Thus, 15-LO-1 metabolites may not on ly serve as ligands for PPAR gamma but can down-regulate PPAR gamma activit y via the MAPK signaling pathway.