Cancer and n–3PUFAs: The Translation Initiation Connection

1. A combination of epidemiological, case–control, and cohort studies in the second half of the past century underscored the possibility that high dietary intake of n–3 polyunsaturated fatty acids (n–3 PUFA) could have a protective effect against cancer. 2. Polyunsaturated fatty acids are classified as having at least 18 carbon chains that are linear and display sequential non-conjugated double bonds separated by single methylene units. The double bonds are solely in the cis configuration, with the two hydrogens and the two methylenes on opposite side of the double bond. The two polyunsaturated fatty acids of importance are linoleic (18:2 n–6) and linolenic (18:3 n–3). 3. Since n–3 PUFA incorporate into and are an integral part of membrane phospholipids they can exert profound effects on its physical properties, including permeability, lateral diffusion, lipid packing, and domain formation, and thereby affect function of membrane proteins intimately involved in intracellular signaling. Consistently, n–3 PUFA have been shown to influence G protein-coupled receptors and receptor tyrosine kinase signaling pathways, and ion channels, a diversity of cellular effects believed to contribute to their anti-cancer properties. 4. The long chain PUFA are highly susceptible to lipid peroxidation. Peroxidation products of the marine fatty acids have been proposed as mediators of their anti-cancer effects. 5. Evolutionary and cultural changes have shifted the human diet over time toward a lower n–3 to n–6 PUFA ratio to the point that the modern Western diet is overwhelmingly rich in n–6 PUFA. The observed increase in cancer rates in populations that until recently still relied on n–3 PUFA-rich diets may be a reflection of the potential impact of the dietary transition from n–3 to n–6 PUFA-rich diets.