Abstract A013: Metabolomics of acute vs. chronic spinach intake in an Apc-mutant genetic background: linoleate and butanoate metabolites targeting HDAC activity and IFN- signaling
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AbstractThere is growing interest in the crosstalk between the gut microbiome, metabolomic features, and disease pathogenesis. Colorectal cancer is a major health burden worldwide, linked in part to modifiable risk factors associated with diet and lifestyle (1). The differential roles of the metabolites in targeting Wnt/b-catenin signaling were recently reported (2). The current investigation compared long-term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wildtype animals corroborated key contributions to anticancer outcomes by spinach-derived linoleate bioactives and a butanoate metabolite linked to increased a-diversity of the gut microbiome (3). Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction observed in colon tumors from rats given long-term spinach treatment. Mechanistic studies in cell-based assays and in vivo implicated the linoleate and butanoate metabolites in targeting histone deacetylase (HDAC) activity and the interferon-g (IFN-g) signaling axis. Clinical translation of the findings from this investigation to at-risk patients might provide valuable quality-of-life benefits by delaying surgical interventions and drug therapies with adverse side effects (4,5).References1. Xi, Y., Xu, P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 2021;14: 1011742. Liu, F. et al. Suppression of membranous LPR5 recycling, Wnt/-catenin signaling, and colon carcinogenesis by 15-LOX-1 peroxidation of linoleic acid in PI3P. Cell Rep 2020;32:108049.3. Chen, Y.-S. et al. Dietary spinach reshapes the gut microbiome in an Apc-mutant genetic background: mechanistic insights from integrated multi-omics. Gut Microbes 2021;13:1972756.4. Ulusan, A.M. et al. Optimization of erlotinib plus sulindac dosing regimens for intestinal cancer prevention in an Apc-mutant model of Familial Adenomatous Polyposis (FAP). Cancer Prev Res (Phila) 2021;14:325-336.5. Samadder, N.J. et al. Association of sulindac and erlotinib vs placebo with colorectal neoplasia in Familial Adenomatous Polyposis: secondary analysis of a randomized clinical trial. JAMA Oncol 2018:4:671-677.Citation Format: Ying-Shiuan Chen, Jia Li, Sultan Neja, Rani Menon, Arul Jayaraman, Kyongbum Lee, Wan Mohaiza Dashwood, Shan Wang, Sabeeta Kapoor, Praveen Rajendran, Ke Zhang, Roderick Dashwood. Metabolomics of acute vs. chronic spinach intake in an Apc-mutant genetic background: linoleate and butanoate metabolites targeting HDAC activity and IFN- signaling [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A013.
