Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress

Marx, C. et al. (2022) Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress. Cancer and Metabolism, 10, 10. (doi: 10.1186/s40170-022-00286-9) (PMID:35787728) (PMCID:PMC9251592)

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Background: Metabolic adaptations can allow cancer cells to survive DNA-damaging chemotherapy. This unmet clinical challenge is a potential vulnerability of cancer. Accordingly, there is an intense search for mechanisms that modulate cell metabolism during anti-tumor therapy. We set out to define how colorectal cancer CRC cells alter their metabolism upon DNA replication stress and whether this provides opportunities to eliminate such cells more efficiently. Methods: We incubated p53-positive and p53-negative permanent CRC cells and short-term cultured primary CRC cells with the topoisomerase-1 inhibitor irinotecan and other drugs that cause DNA replication stress and consequently DNA damage. We analyzed pro-apoptotic mitochondrial membrane depolarization and cell death with flow cytometry. We evaluated cellular metabolism with immunoblotting of electron transport chain (ETC) complex subunits, analysis of mitochondrial mRNA expression by qPCR, MTT assay, measurements of oxygen consumption and reactive oxygen species (ROS), and metabolic flux analysis with the Seahorse platform. Global metabolic alterations were assessed using targeted mass spectrometric analysis of extra- and intracellular metabolites. Results: Chemotherapeutics that cause DNA replication stress induce metabolic changes in p53-positive and p53-negative CRC cells. Irinotecan enhances glycolysis, oxygen consumption, mitochondrial ETC activation, and ROS production in CRC cells. This is connected to increased levels of electron transport chain complexes involving mitochondrial translation. Mass spectrometric analysis reveals global metabolic adaptations of CRC cells to irinotecan, including the glycolysis, tricarboxylic acid cycle, and pentose phosphate pathways. P53-proficient CRC cells, however, have a more active metabolism upon DNA replication stress than their p53-deficient counterparts. This metabolic switch is a vulnerability of p53-positive cells to irinotecan-induced apoptosis under glucose-restricted conditions. Conclusion: Drugs that cause DNA replication stress increase the metabolism of CRC cells. Glucose restriction might improve the effectiveness of classical chemotherapy against p53-positive CRC cells.

Item Type:Articles
Additional Information:Funding: Open Access funding enabled and organized by Projekt DEAL. This project was funded by DFG project RTG1715 SP13 (to O.H.K.). C.M. had additional funding from Boehringer Ingelheim Fonds (BIF) and Richard Winter Stiftung (both to C.M.). ODKM was funded by CRUK Career Development Fellowship C53309/A19702. L.M-B. was supported by a scholarship of the Graduate Acad‑ emy (GA) of the Friedrich Schiller University (FSU) Jena. Work done in the lab of O.H.K. is supported by the Deutsche Forschungsgemeinschaft KR2291/9–1, project number 427404172/12–1, project number 445785155/14–1, project number 469954457/15–1, project number 495271833, project number 496927074/16–1, DFG-project number 393547839—SFB 1361, sub-project 11, the Wilhelm Sander-Stiftung (2019.086.1), and the Brigitte und Dr. Konstanze Wegener-Stiftung (Projekt #65).
Keywords:Research, Adaptation, Colorectal cancer, Glucose, Irinotecan, Metabolism, p53, Warburg effect
Glasgow Author(s) Enlighten ID:Maddocks, Professor Oliver
Authors: Marx, C., Sonnemann, J., Maddocks, O. D. K., Marx-Blümel, L., Beyer, M., Hoelzer, D., Thierbach, R., Maletzki, C., Linnebacher, M., Heinzel, T., and Krämer, O. H.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer and Metabolism
Publisher:BioMed Central
ISSN (Online):2049-3002
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cancer and Metabolism 10: 10
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171982Targeting Tumour Metabolism for Cancer Therapy and Diagnosis.Oliver MaddocksCancer Research UK (CRUK)C53309/A19702Institute of Cancer Sciences