Effect of Altering Dietary ω-6/ω-3 Fatty Acid Ratios on Prostate Cancer Membrane Composition, Cyclooxygenase-2, and Prostaglandin E2

Abstract

Purpose: To determine whether altering the dietary content of ω-6 (n-6) and ω-3 (n-3) polyunsaturated fatty acids affects the growth of androgen-sensitive prostate cancer xenografts, tumor membrane fatty acid composition, and tumor cyclooxygenase-2 and prostaglandin E2 (PGE2) levels. Experimental Design: Individually caged male severe combined immunodeficiency mice were fed isocaloric 20% kcal fat diets with the fat derived either primarily from n-6 fatty acids (n-6 group) or with the fat consisting of n-6 and n-3 fatty acids in a ratio of 1:1 (n-3 group), and injected s.c. with Los Angeles Prostate Cancer 4 (LAPC-4) cells. Tumor volumes and mouse weights were measured weekly, caloric intake was measured 3 days per week, and tumors and serum were harvested at 8 weeks postinjection. Results: Tumor growth rates, final tumor volumes, and serum prostate-specific antigen levels were reduced in the n-3 group relative to the n-6 group. The n-3 group tumors had decreased proliferation (Ki67 staining) and increased apoptosis (terminal nucleotidyl transferase–mediated nick end labeling staining). In vitro proliferation of LAPC-4 cells in medium containing n-3 group serum was reduced by 22% relative to LAPC-4 cells cultured in medium containing serum from the n-6 group. The n-6/n-3 fatty acid ratios in serum and tumor membranes were lower in the n-3 group relative to the n-6 group. In addition, n-3 group tumors had decreased cyclooxygenase-2 protein and mRNA levels, an 83% reduction in PGE2 levels, and decreased vascular endothelial growth factor expression. Conclusion: These results provide a sound basis for clinical trials evaluating the effect of dietary n-3 fatty acids from fish oil on tumor PGE2 and membrane fatty acid composition, and serum and tumor biomarkers of progression in men with prostate cancer.

Dietary n-3 Polyunsaturated Fatty Acids Enhance Hormone Ablation Therapy in Androgen-Dependent Prostate Cancer

“…This inconsistency may be related to the distinct models used and/or differences in experimental design. For instance, Kobayashi and colleagues 38 recently reported that growth of hormone-dependent prostatic LAPC-4 xenograft tumors was inhibited by replacing 50% of dietary fat (corn oil) with fish oil. In contrast to CWR22 tumors, the LAPC-4 cells were shown to express COX-2 and produce PGE 2 , which is a known cell-survival pathway in cancer inhibited by n-3 PUFA, and we examined the affects of dietary PUFA on established tumors rather than their establishment and subsequent growth.…”

Arachidonic acid modulates the crosstalk between prostate carcinoma and bone stromal cells

“…In particular, dietary n-6/n-3 fatty acid ratio seems to control not only the membrane fatty acid composition but also the growth of PCa xenografts in preclinical models (Kobayashi et al 2006). Therefore, we may propose that PCa cells over-producing LOX and COX enzymes are able to take an important advantage for their growth from the presence of elevated concentrations of AA in their microenvironment.…”

“…However, a strict relationship between the amount of available AA in the membrane and the diet exists. In fact, as demonstrated by preclinical studies, intake of dietary n-6 fatty acid regulates the levels of AA not only in serum but also in membrane phospholipids (Kobayashi et al 2006). AA is metabolized via either the cyclooxygenase (COX) or lipoxygenase (LOX) pathway producing prostaglandins and hydroperoxyeicosatetraenoic acids (HETEs) respectively.…”

Should animal fats be back on the table? A critical review of the human health effects of animal fat

“…Is it just that increased food consumption has resulted in higher BMI, which of itself predisposes the individual to these disorders, or is it truly the type of fat? Mechanistic studies of n-3 and n-6 fats show their role in respectively inhibiting and promoting inflammation and tumour growth (Xia et al 2005;Kobayashi et al 2006), while high levels of n-6 fats may inhibit the action of delta-9 desaturase (Yang et al 1999b), critical for desaturating SFA. So while controlling bodyweight may be the more important strategy, reducing the level of n-6 PUFA to bring down the OMR of the diet appears worthwhile.…”