| Conjugated linoleic acid (CLA) is a group of geometric isomers of linoleic acid that have been shown to reduce tumorigenesis in the breast, prostate, stomach, and colon of animal models. However, its mechanism of action is not clearly understood. Several hypotheses were suggested by investigators and one of those was alteration of eicosanoid metabolism by CLA. Therefore, I hypothesized that CLA modulates mammary tumor growth by alteration of cell proliferation and apoptosis as well as vascular endothelial growth factor (VEGF) production through modulation of eicosanoid metabolism.; The isomers, t10, c12-CLA but not c9, t11-CLA, reduced murine mammary tumor cell viability in a dose and time dependent manner and decreased 5-hydroxyeicosatetraenoic acid (5-HETE) production. Adding back 5-HETE to the tumor cells reduced the t10, c12-CLA effect on apoptosis and cell proliferation. These results indicated that t10, c12-CLA altered mammary tumor cell growth by suppression of 5-HETE production. Thus, we determined how t10, c12-CLA modulated the 5-lipoxygenase metabolite, 5-HETE, production.; The t10, c12-CLA isomer altered human mammary tumor cell viability in a dose dependent manner and reduced 5-HETE production but not 15- and 12-HETE production. t10, c12-CLA was not metabolized by lipoxygenase but acted in competition with the lipoxygenase substrate, arachidonic acid, in vitro and reduced five-lipoxygenase activating protein (FLAP) expression. Over-expressed FLAP reduced t10, c12-CLA effect on cell viability.; We also sought to determine whether CLA would alter VEGF production which in turn could alter vascularization of the tumor. c9, t11-CLA but not t10, c12-CLA reduced VEGF expression and secretion from hypoxia-induced and PMA-stimulated murine mammary tumor cells. Several studies have shown that PGE2 stimulated VEGF expression in tumors. CLA treated tumor cells reduced cyclooxygenase (COX) -1 and -2 expressions and reduced PGE2 production. Thus, CLA may modulate breast tumorigenesis by alteration of cell proliferation and apoptosis and vascularization by reduction of VEGF expression through alteration of the eicosanoid pathway. |
