Author:
Holt Amy K.,Najumudeen Arafath K.,Collard Tracey J.,Li Hao,Millett Laura M.,Hoskin Ashley J.,Legge Danny N.,Mortensson Eleanor M. H.,Flanagan Dustin J.,Jones Nicholas,Kollareddy Madhu,Timms Penny,Hitchings Matthew D.,Cronin James,Sansom Owen J.,Williams Ann C.,Vincent Emma E.
Abstract
Abstract
Background
To 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.
Methods
We 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.
Results
We 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.
Conclusions
Together, 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.
Funder
James Tudor Foundation
John James Bristol Foundation
Cancer Research UK
Diabetes UK
Medical Research Council
Bowel and Cancer Research
Cancer research uk
European Research Council
World Cancer Research Fund
Publisher
Springer Science and Business Media LLC
Reference61 articles.
1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
2. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200.
3. Mates JM, Di Paola FJ, Campos-Sandoval JA, Mazurek S, Marquez J. Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer. Semin Cell Dev Biol. 2020;98:34–43.
4. Chambers AC, Dixon SW, White P, Williams AC, Thomas MG, Messenger DE. Demographic trends in the incidence of young-onset colorectal cancer: a population-based study. Br J Surg. 2020;107(5):595–605.
5. Cancer Research UK. Bowel cancer statistics. 2018. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer.