Long chain omega-3 fatty acids and their oxidized metabolites are associated with reduced prostate tumor growth

Cancer has been associated with increased oxidative stress and deregulation of bioactive oxylipins derived from long-chain polyunsaturated fatty acids (LC-PUFA) like arachidonic acid (AA). There is a debate whether ω-3 LC-PUFA could promote or prevent prostate tumor growth through immune modulation and reduction of oxidative stress. Our aim was to study the association between enzymatically or non-enzymatically produced oxidized-LC-PUFA metabolites and tumor growth in an immune-competent eugonadal and castrated C57BL/6 male mice injected with TRAMP-C2 prostate tumor cells, fed with ω-3 or ω-6 LC-PUFA-rich diets.

Tumor fatty acids were profiled by gas chromatography and 26 metabolites derived from either AA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were assessed by liquid chromatography-mass spectrometry.

The enriched ω-3 diet did not reduce oxidative stress overall in tumors but favored the formation of ω-3 rather than ω-6 derived isoprostanoids. We discovered that EPA and its oxidized-derivatives like F₃-isoprostanes and prostaglandin (PG)F_3α, were inversely correlated with tumor volume (spearman correlations and T-test, p<0.05). In contrast, F₂-isoprostanes, adrenic acid, docosapentaenoic acid (DPA_ω-6) and PGE₂ were positively correlated with tumor volume. Interestingly, F₄-neuroprostanes, PGD₂, PGF_2α, and thromboxane were specifically increased in TRAMP-C2 tumors of castrated mice compared to those of eugonadal mice.

Decreasing tumor growth under ω-3 diet could be attributed in part to increased levels of EPA and its oxidized-derivatives, a reduced level of pro-angiogenic PGE₂ and increased levels of F₄-neuroprostanes and resolvins content in tumors, suspected of having anti-proliferative and anti-inflammatory effects.