Attenuation of breast tumor cell growth by conjugated linoleic acid via inhibition of 5-lipoxygenase activating protein.
Conjugated linoleic acid (CLA) consists of a group of linoleic acid geometric isomers that have been shown to reduce tumor growth and metastasis in animal models of breast, prostate and colon cancer. To delineate a possible mechanism of action for CLA, we have recently shown that the 5-lipoxygenase product, 5-hydroxyeicosatetraenoic acid (5-HETE), could play a role in CLA alteration of mammary tumorigenesis. In this study, we determined how CLA could modulate 5-lipoxygenase activity. The t10, c12-CLA isomer reduced production of 5-HETE but not 12- and 15-HETE in MDA-MB-231 human breast tumor cells. That isomer and the c9, t11-CLA isomer decreased 5-HETE production by competition with the lipoxygenase substrate, arachidonic acid (AA). Interestingly, t10, c12-CLA reduced the expression of five-lipoxygenase activating protein (FLAP) but not the 5-lipoxygenase enzyme. Over-expression of FLAP abrogated t10, c12-CLA-reduced viability of MDA-MB-231 cells. These data suggest that the reduction of 5-HETE by t10, c12-CLA was due to competition with AA and the reduction of FLAP expression.
Kim
Jung-Hyun
JH
Department of Cell Biology and Human Anatomy, University of California, School of Medicine, Davis, CA 95616-8643, USA.
Hubbard
Neil E
NE
Ziboh
Vincent
V
Erickson
Kent L
KL
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D007536:Isomerism; D008041:Linoleic Acids / Q000378:metabolism; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics*; D014162:Transfection
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D006893:Hydroxyeicosatetraenoic Acids; D008041:Linoleic Acids; D044243:Linoleic Acids, Conjugated; D008565:Membrane Proteins; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase