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A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites

Author

Listed:
  • Stefan Reich

    (University of Regensburg)

  • Chi D. L. Nguyen

    (Leibniz-Institut für Analytische Wissenschaften—ISAS—e.V.)

  • Canan Has

    (Leibniz-Institut für Analytische Wissenschaften—ISAS—e.V.
    Technical University Dresden)

  • Sascha Steltgens

    (Heinrich Heine University Düsseldorf)

  • Himanshu Soni

    (German Cancer Research Center (DKFZ))

  • Cristina Coman

    (University of Vienna)

  • Moritz Freyberg

    (University of Regensburg)

  • Anna Bichler

    (University of Regensburg)

  • Nicole Seifert

    (University of Regensburg)

  • Dominik Conrad

    (University of Regensburg)

  • Christiane B. Knobbe-Thomsen

    (Heinrich Heine University Düsseldorf)

  • Björn Tews

    (German Cancer Research Center (DKFZ)
    AbbVie Deutschland GmbH & Co.KG)

  • Grischa Toedt

    (European Molecular Biology Laboratory (EMBL))

  • Robert Ahrends

    (Leibniz-Institut für Analytische Wissenschaften—ISAS—e.V.
    University of Vienna)

  • Jan Medenbach

    (University of Regensburg)

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.

Suggested Citation

  • Stefan Reich & Chi D. L. Nguyen & Canan Has & Sascha Steltgens & Himanshu Soni & Cristina Coman & Moritz Freyberg & Anna Bichler & Nicole Seifert & Dominik Conrad & Christiane B. Knobbe-Thomsen & Björ, 2020. "A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16747-y
    DOI: 10.1038/s41467-020-16747-y
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    Cited by:

    1. Taewon Kang & Md Mamunul Haque & Boran Lee & Kyung Tae Hong & Seong Cheol Hong & Younghun Kim & Jesang Lee & Jun-Seok Lee & Dongwhan Lee, 2022. "Orthogonally-tunable and ER-targeting fluorophores detect avian influenza virus early infection," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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