Abstract
Colorectal cancer (CRC) is preceded by the formation of benign polyps, presentingopportunities for effective prevention. Aspirin reduces CRC risk and mortality but its
use for prevention is limited by adverse side effects. 5-aminosalicylic acid (5-ASA) is
an ‘aspirin-like drug’ used clinically for the management of ulcerative colitis and
importantly, is well-tolerated. 5-ASA is reported to reduce the risk of colitis-associated
cancer and has shown promise for prevention of sporadic CRC. However, the safe
implementation of 5-ASA in CRC prevention/therapy necessitates a deeper
understanding of its mechanism of actions.
An important ‘Hallmark of Cancer’ recently shown to be regulated by aspirin is the
reprogramming of cellular metabolism; this is essential to support the increased
demand for biosynthetic intermediates, reducing equivalents, and ATP, which drives
CRC initiation and progression. This study aimed to explore the effect of 5-ASA on
metabolic reprogramming in colorectal cancer cells. Similar to aspirin, proteomic
analysis of 5-ASA treated colorectal adenoma and carcinoma cells identified cellular
metabolism as being significantly regulated. This project describes the effect of 5-ASA
versus aspirin on metabolic enzyme regulation, nutrient utilisation, and the rate of ATP
generating pathways. Unlike aspirin, 5-ASA demonstrated a clear decrease in glucose
utilisation and a concomitant increase in glutamine utilisation; this led to a reduction in
glycolytic rate and oxidative phosphorylation in adenoma derived cells. Kinomic
profiling identified ERK5 as a potential key effector of 5-ASA induced metabolic
changes in early-stage CRC cells.
This work provides insight into a novel mechanism of 5-ASA in colorectal cancer. By
preventing the increase in glucose metabolism in colorectal adenoma cells, 5-ASA
could inhibit aberrant metabolic reprogramming required for tumour progression. This
work supports the translation of 5-ASA as a safe, affordable preventative agent for
colorectal cancer which could be of great benefit, particularly for individuals unable to
tolerate aspirin.
| Date of Award | 17 Jun 2025 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Emma E Vincent (Supervisor) & Ann C Williams (Supervisor) |