A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites
Year: 2020
Type: article
Abstract: Stress response pathways are critical for cellular homeostasis, promoting survival through adaptive changes in gene expression and metabolism. They play key roles in numerous diseases and are implicated in cancer progression and chemoresistance. However, the underlying mechanisms are only poorly understood. We have employed a multi-omics approach to monitor changes to gene expression after induction of a stress response pathway, the unfolded protein response (UPR), probing in parallel the transcriptome, the proteome, and changes to translation. Stringent filtering reveals the induction of 267 genes, many of which have not previously been implicated in stress response pathways. We experimentally demonstrate that UPR-mediated translational control induces the expression of enzymes involved in a pathway that diverts intermediate metabolites from glycolysis to fuel mitochondrial one-carbon metabolism. Concomitantly, the cells become resistant to the folate-based antimetabolites Methotrexate and Pemetrexed, establishing a direct link between UPR-driven changes to gene expression and resistance to pharmacological treatment.
Source: Nature Communications
Institutions: University of Regensburg, Leibniz Institute for Analytical Sciences - ISAS, Technische Universität Dresden, Heinrich Heine University Düsseldorf, German Cancer Research Center, University of Vienna, AbbVie (Germany), European Molecular Biology Laboratory, European Molecular Biology Laboratory
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,621
Awards: G1017261758, de.NBI - Partner - LIFS, 'Juniorverbünde in der Systemmedizin': Systembiologie der ungefalteten Proteinantwort in Gliomen (SUPR-G), EMBL Heidelberg: Konstruktion, Vergleich und Anwendung von ungefalteter Proteinantwort (UPR), ER-Stress bezogenen Netzwerken und Vorhersagen von UPR-System Verhalten, G2495073160, G3254877218, 'Juniorverbünde in der Systemmedizin': Systembiologie der ungefalteten Proteinantwort in Gliomen (SUPR-G), Universität Düsseldorf: Die Bedeutung der ungefalteten Proteinantwort in infiltrierenden Gliomzellen, 'Juniorverbünde in der Systemmedizin': Systembiologie der ungefalteten Proteinantwort in Gliomen (SUPR-G), Universität Regensburg: Quantitative Analyse der globalen Translation während der 'Unfolded Protein Response' in Gliomen, 'Juniorverbünde in der Systemmedizin': Systembiologie der ungefalteten Proteinantwort in Gliomen (SUPR-G), Leibniz-Institut Dortmund: Ein systembiologischer Ansatz zur Bestimmung des Equilibriums der ungefalteten Proteinantwort, G453056226, G5448141689, G648564533, 'Juniorverbünde in der Systemmedizin': Systembiologie der ungefalteten Proteinantwort in Gliomen (SUPR-G), DKFZ Heidelberg: Funktionale Charakterisierung pro-invasiver sekretierter Proteine in Gliomen
OpenAlex ID: W3033734675