Use of Diet/Microbial Bioactive Amphiphiles to Target DNA Damaged Stem Cells
Projects in this research area are designed to assess how the chemoprotective properties of dietary lipid are altered when a highly fermentable fiber, pectin, rather than a poorly fermentable fiber, cellulose, is added to the diet. This protective effect is mediated in part by the up-regulation of targeted apoptosis of DNA adducts during tumor initiation. Our findings indicate that highly fermentable fiber, which generates butyrate in the colon, only has chemotherapeutic value when n-3 PUFA is the lipid source. With respect to a molecular mechanism of action, n-3 PUFA and butyrate (a microbial fermentation product), in combination, synergistically induce a novel p53-independent, oxidation-sensitive, mitochondrial Ca2+-dependent (intrinsic) pathway. This critical observation emphasizes the need to examine both the lipid and fiber composition of diets. The lab is now focusing on the impact of gut-related metabolites on intestinal stem cell biology in vivo and ex vivo using a colonic organoid model system.
- Kim E, Wright GA, Zoh RS, Patil BS, Jayaprakasha GK, Callaway ES, Ivanov I, Turner ND, Chapkin RS. Establishment of a multicomponent dietary bioactive human equivalent dose to delete damaged Lgr5+ stem cells using a mouse colon tumor initiation model. Eur J Cancer Prev. 2018 Sep 18. doi:10.1097/CEJ.0000000000000465. [Epub ahead of print] PubMed PMID: 30234553.
- Chapkin RS. Robert Chapkin on Relationships Between the Gut Microbiome, Diet, and Colorectal Cancer. Oncology (Williston Park). 2018 May 15;32(5):248-9. PubMed PMID: 29847856.
- Triff, M. McLean, E. Callaway, J. Goldsby, I. Ivanov and R.S. Chapkin. Dietary fat and fiber interact to uniquely modify global histone post-translational epigenetic programming in a rat colon cancer progression model. International Journal of Cancer (In Press).
- Triff, M. McLean, K. Konganti, J. Pang, E. Callaway, B. Zhou, I. Ivanov and R.S. Chapkin. Assessment of histone tail modifications and transcriptional profiling during colon cancer progression reveals a global decrease in H3K4me3 activity. Biochimica et Biophysica Acta – Molecular Basis of Disease 1863:1392-1402, 2017. PMID:28315775. PMCID: PMC5474136
- Kim, L.A. Davidson, R.S. Zoh, M.E. Hensel, M.L. Salinas, Patil BS, Jayaprakasha GK, Callaway ES, Allred CD, Turner ND, Weeks BR, Chapkin RS. Rapidly cycling Lgr5+ stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk. Cell Death Dis. 2016;7(11):e2460. PMID: 27831561 PMC5260883.
- A. Davidson, E. Callaway, E. Kim, B. Weeks, Y.Y. Fan, C.D. Allred and R.S. Chapkin. Targeted deletion of p53 in Lgr5-expressing intestinal stem cells promotes colon tumorigenesis in a preclinical model of colitis-associated cancer. Cancer Research 75:5392-5397, 2015. PMID:26631266 PMC4681667
- Shah, E. Kim, L.A. Davidson, J.M. Knight, R. Zoh, J.S. Goldsby, E.S. Callaway, B. Zhou, I. Ivanov and R.S. Chapkin. Comparative effects of diet and carcinogen on mircoRNA expression in the stem cell niche of the mouse colonic crypt. Biochimica et Biophysica – Molecular Basis for Disease 1862:121-134, 2015. PMID:26493444 PMC4674324
- S. Kolar, R. Barhoumi, J.R. Lupton and R.S. Chapkin. Docosahexaenoic acid and butyrate synergistically induce colonocyte apoptosis by enhancing mitochondrial Ca2+ accumulation. Cancer Research 67:561-5568, 2007. PMID:17545640.