Purpose: Omega-3 (n-3) fatty acids (FA) have been proposed to confer tumor-inhibitory properties. In vivo, dietary FA are delivered to tumor cells by two main routes: low-density lipoproteins (LDL) and albumin complexes. High FA concentration in LDL and up-regulation of LDL receptors in tumor cells suggest that the LDL receptor pathway may be the major route for FA delivery. We compared effects of n-3FA delivered to human cancer cells by LDL and albumin.

Experimental Design: LDL was isolated from plasma of African Green monkeys fed diets enriched in fish oil (n-3 FA) or linoleic acid (n-6FA) and used to deliver FA to MCF-7 and PC3 cancer cells. Cell proliferation, apoptosis, and changes in global gene expression were monitored.

Results: Both LDL and albumin were effective in delivering FA to tumor cells and modifying the composition of cell phospholipids. The molar ratio of 20:4 (n-6) to 20:5 (n-3) in phosphatidylcholine and phosphatidylethanolamine was profoundly decreased. Although cell phospholipids were similarly modified by LDL and albumin-delivered FA, effects on cell proliferation and on transcription were markedly different. LDL-delivered n-3 FA were more effective at inhibiting cell proliferation and inducing apoptosis. Expression microarray profiling showed that a significantly higher number of genes were regulated by LDL-delivered than albumin-delivered n-3 FA with little overlap between the two sets of genes.

Conclusions: These results show the importance of the LDL receptor pathway in activating molecular mechanisms responsible for the tumor inhibitory properties of n-3FA.