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

Human colon tumors have elevated levels of 15-lipoxygenase-1 (15-LO-1), suggesting that 15-LO-1 may play a role in the development of colorectal cancer. Also, 15-LO-1 metabolites can up-regulate epidermal growth factor signaling pathways, which results in an increase in mitogenesis. However, metabolites of 15-LO-1 can serve as ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma), and activation of this receptor causes most colon cancer cell lines to undergo a differentiative response and reverse their malignant phenotype. Hence, the role 15-LO-1 plays in colon cancer is not 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 gamma was investigated. In HCT-116 cells, exogenously added 15-LO-1 metabolites, 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. Furthermore, in stable overexpressing 15-LO-1 HCT-116 cells, which produce endogenous 15-LO-1 metabolites, an up-regulation in mitogen-activated protein kinase and PPAR gamma phosphorylation was observed. Incubation with a MAPK inhibitor ablated MAPK and PPAR gamma phosphorylation. The 15-LO-1 up-regulates MAPK activity and increases PPAR gamma phosphorylation, resulting in a down-regulation of PPAR gamma activity. Thus, 15-LO-1 metabolites may not only serve as ligands for PPAR gamma but can down-regulate PPAR gamma activity via the MAPK signaling pathway.