Jean-François Bilodeau1, Nikunj Gevariya2, Jessica Larose3, Karine Robitaille2, Jérôme Roy4, Camille Oger5, Jean-Marie Galano5, Alain Bergeron6, Thierry Durand5, Yves Fradet6, Pierre Julien7, Vincent Fradet8. 1. Axe endocrinologie et néphrologie, Centre de recherche du CHU de Québec - Université Laval, Québec, QC, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada. 2. Laboratoire d'Uro-Oncologie Expérimentale, Centre de Recherche du CHU de Québec - Université Laval, site L'Hôtel-Dieu de Québec, Québec, QC, Canada. 3. Axe endocrinologie et néphrologie, Centre de recherche du CHU de Québec - Université Laval, Québec, QC, Canada. 4. Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Département de Nutrition, Université de Montréal, Montréal, QC, Canada. 5. Institut des Biomolécules Max Mousseron (IBMM), CNRS UMR 5247, Université de Montpellier, ENSCM, Montpellier, France. 6. Laboratoire d'Uro-Oncologie Expérimentale, Centre de Recherche du CHU de Québec - Université Laval, site L'Hôtel-Dieu de Québec, Québec, QC, Canada; Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, QC, Canada; Centre de Recherche sur le cancer de l'Université Laval, Québec, QC, Canada. 7. Axe endocrinologie et néphrologie, Centre de recherche du CHU de Québec - Université Laval, Québec, QC, Canada; Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada; Centre de Recherche sur le cancer de l'Université Laval, Québec, QC, Canada. 8. Laboratoire d'Uro-Oncologie Expérimentale, Centre de Recherche du CHU de Québec - Université Laval, site L'Hôtel-Dieu de Québec, Québec, QC, Canada; Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, QC, Canada; Centre de Recherche sur le cancer de l'Université Laval, Québec, QC, Canada; Centre Nutrition, santé et société (NUTRISS) et Institut sur la nutrition et les aliments fonctionnels (INAF), Québec, Canada. Electronic address: Vincent.Fradet@fmed.ulaval.ca.
Abstract
INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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)F3α, were inversely correlated with tumor volume (spearman correlations and T-test, p<0.05). In contrast, F2-isoprostanes, adrenic acid, docosapentaenoic acid (DPAω-6) and PGE2 were positively correlated with tumor volume. Interestingly, F4-neuroprostanes, PGD2, PGF2α, and thromboxane were specifically increased in TRAMP-C2 tumors of castrated mice compared to those of eugonadal mice. DISCUSSION: 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.
INTRODUCTION: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. MATERIALS AND METHODS: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. RESULTS: 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)F3α, were inversely correlated with tumor volume (spearman correlations and T-test, p<0.05). In contrast, F2-isoprostanes, adrenic acid, docosapentaenoic acid (DPAω-6) and PGE2 were positively correlated with tumor volume. Interestingly, F4-neuroprostanes, PGD2, PGF2α, and thromboxane were specifically increased in TRAMP-C2 tumors of castrated mice compared to those of eugonadal mice. DISCUSSION: 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.