Although a causal role of genetic alterations in human cancer is well established, it is still unclear whether dietary fat can modulate cancer risk in a predisposed population. Epidemiological studies suggest that diets rich in omega-3 polyunsaturated fatty acids reduce cancer incidence. To determine the influence of fatty acids on prostate cancer risk in animals with a defined genetic lesion, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and diets with defined polyunsaturated fatty acid levels. We found that omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival, whereas omega-6 fatty acids had opposite effects. Introducing an omega-3 desaturase, which converts omega-6 to omega-3 fatty acids, into the Pten-knockout mice reduced tumor growth similarly to the omega-3 diet. Tumors from mice on the omega-3 diet had lower proportions of phosphorylated Bad and higher apoptotic indexes compared with those from mice on omega-6 diet. Knockdown of Bad eliminated omega-3-induced cell death, and introduction of exogenous Bad restored the sensitivity to omega-3 fatty acids. Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer.

Although the results from our study suggest phytanic acid levels may be associated with prostate cancer risk, they were based on a study with a small sample size. Much larger studies are required to confirm these important findings.

Epidemiologic studies have suggested for decades an association between dietary fat and cancer risk. A large body of work performed in tissue culture and xenograft models of cancer supports an important role of various types of fat in modulating the cancer phenotype. Yet, the molecular mechanisms underlining the effects of fat on cancer initiation and progression are largely unknown. The relationships between saturated fat, polyunsaturated fat, cholesterol or phytanic acid with cancer have been reviewed respectively. However, few have considered the relationship between all of these fats and cancer. The purpose of this review is to present a more cohesive view of dietary fat-gene interactions, and outline a working hypothesis of the intricate connection between fat, genes and cancer.

Low-density lipoprotein (LDL) oxidation was studied using copper or the water-soluble initiator azobis(2-amidinopropane) dihydrochloride (ABAP) to catalyze the reaction. These studies were carried out with purified, native LDLs that had a well-defined composition and which contained different concentrations of polyunsaturated fatty acids (PUFA) and alpha-tocopherol. The LDL was obtained from nonhuman primates fed diets enriched in cholesterol and one of four types of fatty acids: saturated (Sat), monounsaturated (Mono), omega-6 (omega-6FA), or omega-3 (omega-3FA) fatty acids. The PUFA concentration of the LDLs depended upon the diet and had the following order: omega-6FA > Sat approximately Mono approximately omega-3FA. Linoleic acid was the predominant PUFA in all of the LDLs. The rates of oxidation were linearly dependent upon the concentration of PUFA. When ABAP was used to initiate oxidation the lag time was linearly related to the amount of alpha-tocopherol. However, with copper catalysis no linear correlation was evident. If the different enrichments were analyzed independently, it was found that copper-catalyzed oxidation of LDLs enriched with omega-6 and omega-3 fatty acids showed a linear correlation between the lag time and the amount of alpha-tocopherol but that LDLs enriched with Sat or Mono fatty acids did not show a correlation. These results demonstrate that the rate of oxidation is dependent upon PUFA concentration and that the ability of alpha-tocopherol to inhibit oxidation depends upon the lipid environment and the mode of initiation.

We report here studies of the synthesis of lyso(bis)phosphatidic acid [L(b)PA] by normal and BCG-elicited rabbit alveolar macrophages. This study was prompted by our earlier observations that 1) alveolar macrophages did not synthesize L(b)PA de novo despite its abundance in these cells, 2) BCG-elicited cells contained only one-quarter the amount of L(b)PA as normal cells, and 3) the turnover of arachidonate in L(b)PA led to hydroxyeicosatetraenoic acid and leukotriene synthesis. We found that exogenous phosphatidylglycerol (PG) was specifically converted to L(b)PA by both types of cells although BCG-elicited cells had only one-quarter the synthetic capacity of normal cells. Other phospholipids were found to become cell associated but were not significantly metabolized. Both glycerol moieties and the phosphate were incorporated into the product L(b)PA. However, substitution of the ester with an alkyl linkage in position 1 blocked the conversion of PG to L(b)PA. Most of the alkylphosphatidylglycerol was converted to phosphatidylcholine and phosphatidylethanolamine. This result implied that catabolism of the acyl group in position 1 was essential for L(b)PA synthesis. Because alveolar macrophages are present in a surfactant-rich milieu, we suggest that surfactant provides a source of PG for macrophage synthesis of L(b)PA in situ. It is interesting that the surfactants from rabbits challenged with BCG have a significant decrease in PG content.