Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment.
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)gamma but not COX-2. Cell growth was suppressed by LA in a dose-dependent manner in IEC6 cells. Three-week 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 PPARgamma. 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 AOM-treated 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 PPARgamma. AOM-treated IEC6 cells formed s.c. tumors in 9 of 12 mice, whereas AOM+LA-treated cells formed no tumor. IEC6 cells showed no remarkable alteration of protein production by AOM treatment, whereas cells treated with AOM+LA showed decreased epidermal growth factor receptor (EGFR) and phospho-EGFR and increased BAX. These findings suggest that LA inhibited AOM-induced transformation of COX-2-negative IEC6 cells, which was possibly mediated with PPARgamma ligands generated by LOX15 from LA.
Sasaki
Takamitsu
T
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan.
Yoshida
Kazuhiro
K
Shimura
Hideo
H
Ichiba
Masayosi
M
Sasahira
Tomonori
T
Shimomoto
Takasumi
T
Denda
Ayumi
A
Kuniyasu
Hiroki
H
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004249:DNA Damage; D066246:ErbB Receptors / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D008024:Ligands; D019787:Linoleic Acid / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D002273:Carcinogens; D008024:Ligands; D016859:Lipoxygenase Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D047495:PPAR gamma; D051028:bcl-2-Associated X Protein; D019787:Linoleic Acid; D001093:Arachidonate 15-Lipoxygenase; D019392:Cytochrome P-450 CYP2E1; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D001397:Azoxymethane