title: 15-lipoxygenase-1 exerts its tumor suppressive role by inhibiting nuclear factor-kappa B via activation of PPAR gamma.
abstract: 15-Lipoxygenase-1 (15-LOX-1) is an enzyme of the inflammatory eicosanoid pathway whose expression is known to be lost in colorectal cancer (CRC). We have previously shown that reintroduction of the gene in CRC cell lines slows proliferation and induces apoptosis (Cimen et al. [2009] Cancer Sci 100: 2283-2291). We have hypothesized that 15-LOX-1 may be anti-tumorigenic by the inhibition of the anti-apoptotic inflammatory transcription factor nuclear factor kappa B. We show here that ectopic expression of 15-LOX-1 gene in HCT-116 and HT-29 CRC cell lines inhibited the degradation of inhibitor of kappa B (IκBα), decreased nuclear translocation of p65 and p50, decreased DNA binding in the nucleus and decreased transcriptional activity of Nuclear factor kappa B (NF-κB). As the 15-LOX-1 enzymatic product 13(S)-HODE is known to be a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, and NF-κB can be inhibited by PPARγ, we examined whether activation of PPARγ was necessary for the abrogation of NF-κB activity. Our data show that the inhibition of both early and late stages of NF-κB activation could rescued by the PPARγ antagonist GW9662 indicating that the inhibition was most likely mediated via PPARγ.
authors.affiliation: Department of Biological Sciences, Middle East Technical University, Ankara 06531, Turkey.
authors.forename: I
authors.initials: I
authors.lastname: Cimen
authors.forename: E
authors.initials: E
authors.lastname: Astarci
authors.forename: S
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000813:Anilides / Q000494:pharmacology; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008041:Linoleic Acids / Q000494:pharmacology / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D020672:I-kappa B Proteins; D008041:Linoleic Acids; D016328:NF-kappa B; D047495:PPAR gamma; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; C024348:13-hydroxy-9,11-octadecadienoic acid; D004247:DNA; D001093:Arachidonate 15-Lipoxygenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3