15-Lipoxygenase-1 Metabolites Down-regulate Peroxisome Proliferator-activated Receptor γ via the MAPK Signaling Pathway

Yoshida

et al. 2005

Intl Journal of Cancer

The effect of linoleic acid (LA) on growth and transformation of IEC6 intestinal cells was examined. IEC6 cells expressed mRNAs of 15-lipooxygenase (LOX15) and peroxisome proliferator-activated receptor (PPAR)c but not COX-2. Cell growth was suppressed by LA in a dose-dependent manner in IEC6 cells. Threeweek treatment with LA provided IEC6 cells a quiescent state. LA-induced growth inhibition was abrogated by exposure to antisense S-oligodeoxynucleotides (S-ODNs) for LOX15 and/or PPARc. In an in vitro carcinogenesis model, IEC6 cells, which had confirmed CYP2E1 expression and activity, were continuously treated with AOM and/or LA for 40 weeks. DNA injury in AOMtreated cells was suppressed to the control level by concurrent LA treatment. Colony formation of AOM-treated cells in soft agar was suppressed by treatment with LA, which was reversed by exposure to antisense S-ODNs for LOX15 and/or PPARc. AOMtreated IEC6 cells formed s.c. tumors in 9 of 12 mice, whereas AOM1LA-treated cells formed no tumor. IEC6 cells showed no remarkable alteration of protein production by AOM treatment, whereas cells treated with AOM1LA showed decreased epidermal growth factor receptor (EGFR) and phospho-EGFR and increased BAX. These findings suggest that LA inhibited AOMinduced transformation of COX-2-negative IEC6 cells, which was possibly mediated with PPARc ligands generated by LOX15 from LA. ' 2005 Wiley-Liss, Inc.Key words: linoleic acid; azoxymethane; colon cancer; transformation; peroxisome proliferator-activated receptor Colorectal cancer is the third most common malignant neoplasm worldwide and the third leading cause of cancer deaths in Japan. 1 The frequency of colon cancer in Japan is continuously increased along with the alteration of lifestyle from traditional Japanese to Western. In particular, the increase of fat intake and decrease of fiber intake have been regarded as the most important nutritional influence on colorectal cancer development. 2,3 Prostaglandins are bioactive lipids derived from the metabolites of membrane PUFAs and play important roles in a number of biologic processes. 4 COX-2-dependent overproduction of PGE 2 is hypothesized to be an important part of sustained proliferative and chronic inflammatory conditions. 5,6 Several in vivo studies hypothesize that a high amount of x-6 PUFA, such as LA, might enhance colorectal carcinogenesis via stimulation of colonic epithelial cell proliferation. 7-10 Indeed, rats treated with AOM and fed a diet supplemented with LA developed more tumors than animals treated with AOM alone. 11 AOM is a potent carcinogen, which induces colorectal cancers at high incidence in rats and mice. Adduct formation (mainly O 6 -methylguanine) by AOM induces point mutations in multiple genes such as K-ras and b-catenin. 12 In the present study, we used AOM as a carcinogen in the in vitro carcinogenesis model.The oxidative metabolites of LA, particularly 9-HODE, 13-HODE and 13-OXO, have biologic effects as PPARg ligands. 13 CLA, a strong ligand for PPARg, has a substantial anticarcin...

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment

Yoshida

et al. 2005

Intl Journal of Cancer

“…In general, SDS-PAGE and Western blotting techniques were carried out as described previously (16). Briefly, treated and control cells groups were washed twice with ice-cold PBS and lysed in protein lysis buffer containing protease and phosphatase inhibitors.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were sonicated three times for 5 seconds each at 50% power for a total protein preparation. Protein content was quantified by the Bradford method as described previously (16). Aliquots of the protein preparation were heated to 70°C in protein sample buffer (Invitrogen, Carlsbad, CA) and separated by a 4 to 12% gradient gel (Invitrogen), according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Induces Apoptosis via Induction of 15-Lipoxygenase-1 in Colorectal Cancer Cells

Hsi¹,

Xi²,

Lotan

et al. 2004

Cancer Research

Self Cite

Journal of Biological Chemistry

“…The chemically stable HETE and HODE metabolites of 15-LOX-1 inhibit purified TrxR enzyme, but our data suggest that the metastable HpETEs and HpODEs, or their rearrangement product 4-HNE, also contribute to the inhibition of TrxR in cells. HETEs or HODEs bind weakly and reversibly with cellular receptors, including PPAR␦ (36) or PPAR␥ (31,32,37,44). If HETEs or HODEs alone were the inhibitory molecules, then TrxR activity should have recovered promptly.…”

mentioning

confidence: 99%

Conditional Expression of 15-Lipoxygenase-1 Inhibits the Selenoenzyme Thioredoxin Reductase

Moos

Cassidy

et al. 2004