Complementary actions of N-3 polyunsaturated fatty acids and soy genistein on prostanoid synthesis in MDA-MB-231 human breast cancer cells
Abstract
Both n-3 polyunsaturated fatty acids (PUFA) and genistein have been demonstrated to exert chemopreventive actions; however, few investigators have evaluated these dietary factors in combination. The hypothesis for this research is that n-3 PUFA and soy genistein synergistically reduce the breast cancer risk by altering cylcooxygenase-2 (COX-2) level and prostaglandin E 2 (PGE2) biosynthesis. To test this hypothesis, the MDA-MB-231 human breast cancer cell line (overexpresses COX-2 gene) was selected as the model for this work. The first study compared the efficiency of α-linolenic acid (18:3n-3, LNA) and stearidonic acid (18:4n-3, SDA) conversion to long-chain (LC) PUFA and their capacity to alter prostanoid synthesis. SDA was more effective than LNA in increasing the concentrations of 20 and 22-carbon n-3 PUFA and reducing the ratio of n-6/n-3 PUFA in the cell. In addition, SDA suppressed the expression of the COX-2 gene to a greater extent than LNA, which was associated with a reduction in the levels of NFκB and PPARγ mRNA. These results suggest that SDA was more effective than LNA in modulating the prostanoid production associated with its greater conversion to LC n-3 PUFA. The second study compared the effects of eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) to arachidonic acid (20:4n-6, AA) on prostanoid synthesis in the presence of genistein. The results of this study demonstrated that n-3 PUFA and genistein synergistically downregulated the expression of COX-2 gene and production of PGE2. The inhibition of PGE2 synthesis by n-3 PUFA and genistein treatment was followed by a concomitant decrease in cancer cell invasiveness. Analysis of the transcription factors involved in the expression of COX-2 gene revealed that n-3 PUFA plus genistein reduced PPARγ protein levels and the expression of NFκB. These findings suggest that n-3 PUFA and genistein act together to suppress PGE2 production and the invasiveness of MDA-MB-231 cells by modulating the expression of COX-2 protein via a mechanism involving PPARγ and NFκB. Therefore, the current investigation indicates that increasing the consumption of n-3 PUFA along with soy genistein may reduce the invasiveness of breast cancer by suppressing prostanoid synthesis and associated molecular targets.
Degree
Ph.D.
Advisors
Watkins, Purdue University.
Subject Area
Food science|Nutrition
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.