Eicosanoids as mediators of linoleic acid-stimulated invasion and type IV collagenase production by a metastatic human breast cancer cell line.
Diets rich in linoleic acid (LA) stimulate the metastasis of MDA-MB-435 human breast cancer cells from the mammary fat pads of nude mice. This omega-6 fatty acid is metabolized to various cyclo-oxygenase and lipoxygenase products, several of which have been previously associated with tumor cell invasion and metastasis. We now report that MDA-MB-435 cells secreted increased levels of prostaglandin E2 (PGE2), and 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE when cultured in the presence of 2.7 microM (0.75 micrograms/ml) LA; 5-HETE secretion was unchanged. The 12-lipoxygenase inhibitor esculetin (20 microM) completely blocked the LA-stimulated 12-HETE secretion. Linoleic acid also increased MDA-MB-435 cell invasion in an in vitro assay; this stimulation was abolished by 20 microM esculetin, but was unaffected by piroxicam, a selective cyclooxygenase inhibitor. The effect of LA on invasion was replicated by 0.1 microM 12-HETE, but not by 5-HETE or PGE2; 15-HETE was stimulatory only at a concentration of 1.0 microM. Zymographic and Northern blot analyses showed that these events are accompanied by the induction of 92 kDa isoform type IV collagenase (metalloproteinase-9) enzymic activity and mRNA expression by exogenous LA and 12-HETE, and their suppression by the 12-lipoxygenase inhibitor. These results suggest that the effects of dietary LA on breast cancer cell metastasis in the nude mouse model are due, at least in part, to enhanced 12-HETE biosynthesis, with an associated increase in proteolytic enzyme activity and tumor cell invasiveness.
Liu
X H
XH
Division of Nutrition and Endocrinology, American Health Foundation, Valhalla, New York 10595, USA.
Connolly
J M
JM
Rose
D P
DP
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001943:Breast Neoplasms / Q000473:pathology*; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D015777:Eicosanoids / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010894:Piroxicam / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D014468:Umbelliferones / Q000494:pharmacology
D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D014468:Umbelliferones; D010894:Piroxicam; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D019787:Linoleic Acid; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; C007628:esculetin