title: Long chain n-3 polyunsaturated fatty acids increase the efficacy of docetaxel in mammary cancer cells by downregulating Akt and PKCε/δ-induced ERK pathways.
abstract: Taxanes can induce drug resistance by increasing signaling pathways such as PI3K/Akt and ERK, which promote survival and cell growth in human cancer cells. We have previously shown that long chain n-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA, 22:6n-3) decrease resistance of experimental mammary tumors to anticancer drugs. Our objective was to determine whether DHA could increase tumor sensitivity to docetaxel by down-regulating these survival pathways. In docetaxel-treated MDA-MB-231 cells, phosphorylated-ERK1/2 levels were increased by 60% in membrane and nuclear compartments, compared to untreated cells. Our data showed that ERK1/2 activation depended on PKC activation since: i) enzastaurin (a pan-PKC inhibitor) blocked docetaxel-induced ERK1/2 phosphorylation ii) docetaxel increased PKC activity by 30% and phosphatidic acid level by 1.6-fold iii) inhibition of PKCε and PKCδ by siRNA resulted in reduced phosphorylated ERK1/2 levels. In DHA-supplemented cells, docetaxel was unable to increase PKCε and δ levels in membrane and nuclear fractions, resulting in diminished ERK1/2 phosphorylation and increased docetaxel efficacy. Reduced membrane level of PKCε and PKCδ was associated with significant incorporation of DHA in all phospholipids, including phosphatidylcholine which is a major source of phosphatidic acid. Additionally, examination of the Akt pathway showed that DHA could repress docetaxel-induced Ser473Akt phosphorylation. In rat mammary tumors, dietary DHA supplementation during docetaxel chemotherapy repressed ERK and Akt survival pathways and in turn strongly improved taxane efficacy. The P-ERK level was negatively correlated with tumor regression. These findings are of potential clinical importance in treating chemotherapy-refractory cancer.
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Chauvin
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France; Hôpital "Bretonneau", CHRU, 2 bd Tonnellé, 37000 Tours, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Goupille
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France.
authors.forename: Charly
authors.initials: C
authors.lastname: Blanc
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Pinault
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Domingo
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Guimaraes
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France; Hôpital "Bretonneau", CHRU, 2 bd Tonnellé, 37000 Tours, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bougnoux
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France; UFR des Sciences Pharmaceutiques, Université François Rabelais de Tours, 31 av Monge, 37200 Tours, France.
authors.forename: Stephan
authors.initials: S
authors.lastname: Chevalier
authors.affiliation: Inserm UMR1069 "Nutrition, Croissance et Cancer" Université François Rabelais, Faculté de Médecine, 10 bd Tonnellé, 37032 Tours, France; UFR des Sciences Pharmaceutiques, Université François Rabelais de Tours, 31 av Monge, 37200 Tours, France. Electronic address: karine.maheo@univ-tours.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Mahéo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008770:Methylnitrosourea; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D004281:Docosahexaenoic Acids; D008770:Methylnitrosourea; D051057:Proto-Oncogene Proteins c-akt; C497258:PRKCD protein, human; C497255:PRKCE protein, human; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Akt; DHA; Docetaxel; ERK; Mammary tumors; PKCδ; PKCε; Tumor sensitization; n-3 LCPUFA