title: The probiotic Propionibacterium freudenreichii as a new adjuvant for TRAIL-based therapy in colorectal cancer.
abstract: TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a well-known apoptosis inducer, which activates the extrinsic death pathway. TRAIL is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by cell resistance to cell death which occurs in approximately 50% of cancer cells. Short Chain Fatty Acids (SCFA) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate and acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. Indeed, we hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, increased pro-apoptotic gene expression (TRAIL-R2/DR5) and decreased anti-apoptotic gene expression (FLIP, XIAP) in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on both death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and caspases (caspase-8, -9 and -3) activation, was lethal on cancer cells but not on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented by P. freudenreichii induced HT29 cells apoptosis and enhanced TRAIL cytotoxic activity, as did P. freudenreichii DMEM culture supernatants or its SCFA metabolites. These results open new perspectives for food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer.
authors.affiliation: INRA, UMR1253 STLO, Science et Technologie du Lait et de l'Œuf, Rennes F-35042, France.|AGROCAMPUS OUEST, UMR1253 STLO, Rennes F-35042, France.|CNIEL/Syndifrais, Paris 09 F-75314, France.|Current address: Research Unit Aliments Bioprocédés Toxicologie Environnements (UR ABTE) EA 4651, Université de Caen Normandie, Caen F-14032, France.
authors.forename: Fabien J
authors.initials: FJ
authors.lastname: Cousin
authors.affiliation: INSERM, UMR1085, Institut de Recherche sur la Santé, l'Environnement et le Travail, Rennes F-35043, France.|Biosit UMS3080, Université de Rennes 1, Rennes F-35043, France.|Current address: Department for Biomedical Molecular Biology, University of Ghent, VIB Inflammation Research Center, Ghent B-9052, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jouan-Lanhouet
authors.affiliation: INSERM, UMR1085, Institut de Recherche sur la Santé, l'Environnement et le Travail, Rennes F-35043, France.|Biosit UMS3080, Université de Rennes 1, Rennes F-35043, France.|INRIA, UMR6074 IRISA, Rennes F-35042, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Théret
authors.affiliation: INSERM, UMRS1180, LabEx LERMIT, Châtenay-Malabry F-92290, France.|Université de Paris Sud, Faculté de Pharmacie, Châtenay-Malabry F-92290, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.affiliation: INSERM, UMR1085, Institut de Recherche sur la Santé, l'Environnement et le Travail, Rennes F-35043, France.|Biosit UMS3080, Université de Rennes 1, Rennes F-35043, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouan
authors.affiliation: INSERM, UMR1085, Institut de Recherche sur la Santé, l'Environnement et le Travail, Rennes F-35043, France.|Biosit UMS3080, Université de Rennes 1, Rennes F-35043, France.
authors.forename: Gwénaëlle
authors.initials: G
authors.lastname: Le Moigne-Muller
authors.affiliation: INSERM, UMR1085, Institut de Recherche sur la Santé, l'Environnement et le Travail, Rennes F-35043, France.|Biosit UMS3080, Université de Rennes 1, Rennes F-35043, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Dimanche-Boitrel
authors.affiliation: INRA, UMR1253 STLO, Science et Technologie du Lait et de l'Œuf, Rennes F-35042, France.|AGROCAMPUS OUEST, UMR1253 STLO, Rennes F-35042, France.
authors.forename: Gwénaël
authors.initials: G
authors.lastname: Jan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D043302:Cultured Milk Products; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019936:Probiotics / Q000494:pharmacology*; D000070002:Propionibacterium freudenreichii / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: Propionibacterium freudenreichii; RNA microarrays; SCFA; TRAIL; colon cancer