Differential Effects of Delivery of Omega-3 Fatty Acids to Human Cancer Cells by Low-Density Lipoproteins versus Albumin

Abstract

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.

Peroxisome Proliferator-Activated Receptor γ–Mediated Up-regulation of Syndecan-1 by n-3 Fatty Acids Promotes Apoptosis of Human Breast Cancer Cells

“…LDLs were isolated from plasma of adult African green (vervet) monkeys fed n-3 PUFA ( fish oil)-enriched diets for 3 to 5 y. Diets, maintenance, and clinical measurements of the animals are published (43). Animal care and procedures were approved by the Animal Care and Use Committee of Wake Forest University School of Medicine, and animals were maintained by standard animal care procedures based on institutional guidelines.…”

“…Animal care and procedures were approved by the Animal Care and Use Committee of Wake Forest University School of Medicine, and animals were maintained by standard animal care procedures based on institutional guidelines. LDL isolation and characterization procedures have been previously described (43). To measure EPA and DHA concentrations in n-3 LDL preparations, 100 AL LDL was added to 20.6 Ag C17:0 (as triheptadecanoate glyceride) and then saponified, extracted, and derivatized by standard procedures.…”

“…In the human breast cancer cell line MCF-7, n-3 PUFA not only inhibited cell proliferation and increased apoptosis but also promoted SDC-1 expression (14,43). The SDC-1 response was mimicked by the PPARg agonist troglitazone and blocked by a PPARg antagonist.…”

Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2

“…As a result, only a fraction of lyso-PC is functionally active, and it is unclear how total concentration relates to bioavailability ( 73,85 ). Similarly, the bioactivity of fatty acids appears to be modulated by the carrier, again underscoring the importance of location on biological activity ( 86,87 ). Thus, whether results generated using lyso-PC and oxidized fatty acids in vitro realistically refl ect in vivo responses remains to be rigorously determined.…”

Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids

“…PC3, LNCaP, LNCaP (vector), and LNCaP (mBad) cells were infected with shRNA lentivirus expressing scrambled shRNA or Bad-specific shRNA or were mock infected for 2 days. Cells (10,000) were seeded in 6-well plates with 1 ml medium with or without 100 μg/ml LDL FAs (15). One milliliter of corresponding fresh medium was added every other day, and cells were incubated for a total of 6 days.…”