Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

Cancer & Metabolism

Research

Dustin J. Flanagan¹  Laura M. Millett¹  Arafath K. Najumudeen²  Owen J. Sansom³  Hao Li⁴  Emma E. Vincent⁵  James Cronin⁶  Matthew D. Hitchings⁶  Nicholas Jones⁶  Tracey J. Collard⁷  Penny Timms⁷  Eleanor M. H. Mortensson⁷  Madhu Kollareddy⁷  Ashley J. Hoskin⁷  Amy K. Holt⁷  Ann C. Williams⁷  Danny N. Legge⁸ 

[1] Cancer Research UK Beatson Institute, G61 1BD, Glasgow, UK;Cancer Research UK Beatson Institute, G61 1BD, Glasgow, UK;Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland;Cancer Research UK Beatson Institute, G61 1BD, Glasgow, UK;Institute of Cancer Sciences, University of Glasgow, G61 1QH, Glasgow, UK;Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland;Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland;MRC Integrative Epidemiology Unit, Oakfield House, University of Bristol, BS8 2BN, Bristol, UK;Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, Swansea, UK;School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, BS8 1TW, Bristol, UK;School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, BS1 3NY, Bristol, UK;

关键词: Colorectal cancer;    Aspirin;    Metabolism;    Metabolic reprogramming;    CB-839;    Glutaminase;   

DOI  :  10.1186/s40170-023-00318-y

 received in 2022-11-21, accepted in 2023-10-07,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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