A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites
Open accessAbstract
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.
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SHMT2 and MTHFD2 expression is increased upon induction of the unfolded protein response (UPR).
“Recently, SHMT2 and MTHFD2 expression was found to be increased upon induction of the unfolded protein response (UPR).218”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [218]
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References 76 · Cited by 90
- Authors
- Reich, S., Nguyen, C. D. L., Has, C., Steltgens, S., Soni, H., Coman, C., Freyberg, M., Bichler, A., Seifert, N., Conrad, D., Knobbe-Thomsen, C. B., Tews, B., Toedt, G., Ahrends, R., & Medenbach, J.
- Affiliations
- University of Regensburg (DE)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Heinrich Heine University Düsseldorf (DE)
- German Cancer Research Center (DE)
- University of Vienna (AT)
- European Molecular Biology Laboratory (DE)
- Corresponding author
- Ahrends, Robert
- Medenbach, Jan
- ORCID
- Venue
- Nature Communications
- Published
- 2020-06-10
- Volume
- 11
- Issue
- 1
- Pages
- 2936-2936
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7287054
- OpenAlex
- W3033734675
- Cited by
- 90
- References
- 76
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 11 · 2023: 10 · 2022: 17 · 2021: 14 · 2020: 4
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Regensburg Publication Server (University of Regensburg)
- Funders
- Joachim Herz Stiftung
- Bundesministerium für Bildung und Forschung (01ZX1401B, 01ZX1401A, 01ZX1401E, 01ZX1401C, 01ZX1401D)
- Deutsche Krebshilfe (110663)
- Deutsche Forschungsgemeinschaft (DFG SFB960/2, B11)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- unfolded protein response, stress response pathways, methotrexate, pemetrexed, chemoresistance, translational regulation, one-carbon metabolism, mitochondrial metabolism, glycolysis, transcriptome, proteome, gene expression regulation, cancer
- MeSH terms
- Pemetrexed, Animals, Antimetabolites, Endoplasmic Reticulum, Folic Acid, Humans, Methotrexate, Signal Transduction, Regulon, Proteome, Unfolded Protein Response, Transcriptome
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