No Cover Image

Journal article 145 views 18 downloads

Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

Amy K. Holt, Arafath K. Najumudeen, Tracey J. Collard, Hao Li, Laura M. Millett, Ashley J. Hoskin, Danny N. Legge, Eleanor M. H. Mortensson, Dustin J. Flanagan, Nick Jones Orcid Logo, Madhu Kollareddy, Penny Timms, Matthew Hitchings Orcid Logo, James Cronin Orcid Logo, Owen J. Sansom, Ann C. Williams, Emma E. Vincent

Cancer and Metabolism, Volume: 11, Issue: 1

Swansea University Authors: Nick Jones Orcid Logo, Matthew Hitchings Orcid Logo, James Cronin Orcid Logo

  • 65574.pdf

    PDF | Version of Record

    This article is licensed under a Creative Commons Attribution 4.0 International License.

    Download (5.14MB)

Abstract

BackgroundTo support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is chall...

Full description

Published in: Cancer and Metabolism
ISSN: 2049-3002
Published: Springer Science and Business Media LLC 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa65574
Tags: Add Tag
No Tags, Be the first to tag this record!
Abstract: BackgroundTo support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.MethodsWe generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.ResultsWe show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.ConclusionsTogether, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.
Keywords: Colorectal cancer, Aspirin, Metabolism, Metabolic reprogramming, CB-839, Glutaminase
College: Faculty of Medicine, Health and Life Sciences
Funders: AKH and AJH were supported by the James Tudor Foundation; AKH, AJH and EMHM were supported by John and Bridget Maynard; and PT was supported by a PhD studentship from Bowel & Cancer Research. AKH, AJH, EMHM and PT were also supported by the John James Bristol Foundation. DF, TJC, OJS and ACW by an MRC Research Grant (MR/R017247/1). EEV and DNL are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). EEV and TJC are supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). AKN was supported by Cancer Research UK (CRUK) Beatson Institute core funding (A17196, A31287)—awarded to OJS. OJS was supported by CRUK grants (A21139, A12481, A17196 and A31287) and ERC Starting grant (311301). LMM is supported by a CRUK Scotland Centre Grant (CTRQQR-2021\100006).
Issue: 1