Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

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...

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Bibliographic Details
Published in:Cancer & metabolism Vol. 11; no. 1; p. 18
Main Authors: 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
Format: Journal Article
Language:English
Published: England BioMed Central Ltd 19-10-2023
BioMed Central
BMC
Subjects:
Apoptosis
Aspirin
Cancer
Cancer therapies
CB-839
Cells
Colorectal cancer
Enzymes
Experiments
Glucose metabolism
Glutaminase
Health aspects
Kinases
Metabolic reprogramming
Metabolism
Oncology, Experimental
Pharmaceutical industry
Prevention
United Kingdom
Germany
United Kingdom > UK
United States > US
Aspirin
Metabolic reprogramming
CB-839
Metabolism
Glutaminase
Colorectal cancer
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Summary: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. 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. 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 Apc mice in vivo. 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.
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ISSN:2049-3002
2049-3002
DOI:10.1186/s40170-023-00318-y