Investigating the effects of aspirin on colorectal cancer cell metabolism

Abstract

Colorectal cancer (CRC) is the second highest cause of cancer-related mortality in the UK and incidence is increasing, particularly in younger patients. 5-year survival rates in CRC cases diagnosed at later stage are particularly low, highlighting a need for effective preventative interventions and improved therapies.

Aspirin has been found in multiple large studies to be effective in reducing CRC risk, particularly when taken for a long period of time. However, potential side[1]effects and complications such as the increased risk of bleeding limit its clinical utility as a prophylactic agent. Further understanding of the mechanisms underlying aspirin’s anti-cancer effects will help optimise benefits from its use, such as improving patient stratification, dosage, timing of treatment and identifying synergistic therapies.

In order to identify novel mechanisms of long-term aspirin exposure, CRC cell lines were previously treated with aspirin long-term (52 weeks). Proteomic analysis of these cells highlighted a potential role for aspirin in regulating cellular metabolism. Metabolic reprogramming is a key aspect of cancer cell biology and work is ongoing to identify methods of targeting cellular metabolism for cancer therapy. Therefore, the focus of this thesis is the role of aspirin in regulating cancer cell metabolism and investigating metabolic vulnerabilities that could be exploited to increase the efficacy of existing therapies.

This project describes the effect of long-term aspirin on regulation of a number of key metabolic enzymes, as well as causing a shift in nutrient utilisation and TCA cycle carbon sources. It was found that aspirin inhibits glutaminolysis and increases utilisation of glucose. Based on these findings, aspirin was subsequently found to increase sensitivity of CRC cell lines to metabolic inhibitors, most notably CB-839, which is currently in clinical trials for a number of different cancer types. This effect was maintained in physiological cell culture medium, suggesting it is likely to be applicable to in vivo conditions.

Findings from this project have highlighted in detail a novel mechanism of action of aspirin on CRC cells, potentially contributing to its function in cancer prevention. Results also suggest that combining aspirin with CB-839 may be an effective clinical approach for treatment of advanced CRC, supporting future clinical trials in patients who currently have limited effective therapeutic options.