Gutenberg Open Science: Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8685

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DC Field	Value	Language
dc.contributor.author	Marx, Christian	-
dc.contributor.author	Sonnemann, Jürgen	-
dc.contributor.author	Maddocks, Oliver D. K.	-
dc.contributor.author	Marx-Blümel, Lisa	-
dc.contributor.author	Beyer, Mandy	-
dc.contributor.author	Hoelzer, Doerte	-
dc.contributor.author	Thierbach, René	-
dc.contributor.author	Maletzki, Claudia	-
dc.contributor.author	Linnebacher, Michael	-
dc.contributor.author	Heinzel, Thorsten	-
dc.contributor.author	Krämer, Oliver H.	-
dc.date.accessioned	2023-02-07T08:12:01Z	-
dc.date.available	2023-02-07T08:12:01Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/8701	-
dc.description.abstract	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 defne how colorectal cancer CRC cells alter their metabolism upon DNA replication stress and whether this provides opportunities to eliminate such cells more efciently. 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 conse‑ quently DNA damage. We analyzed pro-apoptotic mitochondrial membrane depolarization and cell death with fow 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 fux 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-profcient CRC cells, however, have a more active metabolism upon DNA replication stress than their p53-defcient 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 efectiveness of classical chemotherapy against p53-positive CRC cells.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-8685	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Cancer & metabolism	de
jgu.journal.volume	10	de
jgu.pages.alternative	10	de
jgu.publisher.year	2022	-
jgu.publisher.name	BioMed Central	de
jgu.publisher.place	London	de
jgu.publisher.issn	2049-3002	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.1186/s40170-022-00286-9	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Lebenswissenschaften	de
Appears in collections:	DFG-491381577-G

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