Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.577449
Title: Systems biology study of distinct actions by short-chain fatty acids in colon cancer cell-lines
Author: Kilner, Jo
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Abstract:
Colorectal cancer (CRC) is the third largest cause of cancer deaths worldwide. Short-chain fatty acids (SCFA) are reported to be chemoprotective against CRC and are beneficial to colon epithelia by virtue of being their preferred energy source. Despite being essential to human metabolism and health, SCFAs are only accessible to humans as nutritional by-products of the anaerobic fermentation of dietary fibre by gut bacteria. Identifying novel chemotherapeutic roles for SCFAs is attractive due to their high tolerance by colonocytes, however the underlying metabolic actions are not fully understood. This project took a Systems Biology approach by employing high-throughput, quantitative proteomic and cellomic experimentation to investigate whether the three principle SCFAs in colon epithelia, butyrate, propionate and valerate, display unique roles with potentially chemoprotective actions. A hypothesised anti-mitotic pathway was formulated in which odd-chain SCFAs at above physiological concentrations induce downstream epigenetic acetylation of transcriptional regulators to differentially regulate β-tubulin isotypes. This creates an aberrant tubulin code leading to the disruption of microtubule (MT) dynamics, failure of critical MT cellular functions and eventual cell death. The pathway was simulated by computational dynamical modelling to predict the behaviour of SCFAs in relation to MT dynamics under both treatment and physiological conditions. This verified the plausibility of the hypothesis and provided valuable insights into the underlying mechanisms. Bioinformatic searches, combined with proteomic evidence, indicated that propionate and valerate, the odd-chain SCFAs, differentially regulated pro-tumourigenic β-tubulin isotypes. The alteration of the β-tubulin expression pattern countered potential metabolic adaptions in colon cancer cells, suggesting a chemopreventive action. Anti-microtubule drugs (AMD) are among the most successful chemotherapies to date, however their toxicity and drug resistance increase with successive rounds of treatment. This project has demonstrated that odd-chain SCFAs may act as novel chemotherapeutics by reducing the negative effects of AMDs while enhancing their efficacy.
Supervisor: Wilkinson, Stephen ; Corfe, Bernard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.577449  DOI: Not available
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