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.
Highlights
Colorectal cancer (CRC), the fourth most frequent cause of cancer deaths worldwide, is tightly linked with lifestyle, including diet [1]
A whole transcriptome analysis was carried out using microarrays, to elucidate the response of HT29 human colon cancer cells to a 6 h treatment combining TNF-Related Apoptosis-Inducing Ligand (TRAIL) (100 ng/ml + 2 μg/ml anti-Flag M2 antibody) with propionibacterial culture supernatant (SN diluted to 1/2) or a mixture of propionate (30 mM) and acetate (15 mM) (C3/C2, the major metabolites used in the amounts present in the diluted SN)
As it has been shown that Short Chain Fatty Acids (SCFA) can modulate histone acetylation [22], we demonstrated that treatment of HT29 cells with SN or C3/C2 alone or in www.impactjournals.com/oncotarget combination with TRAIL led to the histone H3 acetylation which may be indicative of a histone deacetylase inhibitory activity present in the supernatant (SN) or the mixture of SCFA (C3/C2) (Figure 4C)
Summary
Colorectal cancer (CRC), the fourth most frequent cause of cancer deaths worldwide, is tightly linked with lifestyle, including diet [1]. Efforts are made to prevent and/or fight CRC using food components, including prebiotics and probiotics In this context, dairy Gram positive propionibacteria, as the probiotic species Propionibacterium freudenreichii (Pf) [2], were shown to induce apoptosis of colon cancer cells via the intrinsic apoptotic death pathway [3, 4]. Dairy Gram positive propionibacteria, as the probiotic species Propionibacterium freudenreichii (Pf) [2], were shown to induce apoptosis of colon cancer cells via the intrinsic apoptotic death pathway [3, 4] These propionibacteria induce apoptosis, via the production of SCFAs, in vitro and in vivo in human microbiota-associated rats [5]. We have shown that the active compounds, SCFAs, are secreted and recovered in the aqueous phase of the fermented dairy product
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