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

Stefan Reich1, Chi D L Nguyen2, Canan Has2,3

  • 1Biochemistry I, University of Regensburg, Regensburg, Germany.

Nature Communications
|June 12, 2020
PubMed

Insights

The unfolded protein response (UPR) activates cellular metabolism changes, leading to resistance against cancer drugs like Methotrexate. This study reveals new UPR-regulated genes and metabolic pathways critical for cell survival and drug resistance.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Stress response pathways are essential for maintaining cellular homeostasis and survival.
  • These pathways are implicated in various diseases, including cancer progression and chemoresistance.
  • The precise molecular mechanisms underlying stress responses, particularly the unfolded protein response (UPR), remain incompletely understood.

Purpose of the Study:

  • To investigate the molecular changes induced by the unfolded protein response (UPR) using a multi-omics approach.
  • To identify novel genes and metabolic pathways regulated by UPR.
  • To establish a link between UPR activation and resistance to specific chemotherapeutic agents.

Main Methods:

  • Utilized a multi-omics strategy, analyzing transcriptome, proteome, and translational changes.
  • Induced the unfolded protein response (UPR) pathway to observe cellular responses.
  • Applied stringent filtering to identify significantly altered genes.

Main Results:

  • Identified 267 induced genes, many previously unrecognized in stress response pathways.
  • Demonstrated UPR-mediated translational control redirects glycolysis metabolites to mitochondrial one-carbon metabolism.
  • Showed that UPR activation confers resistance to folate-based antimetabolites, Methotrexate and Pemetrexed.

Conclusions:

  • The unfolded protein response (UPR) significantly alters cellular metabolism by influencing gene expression and translation.
  • UPR activation provides a survival advantage by conferring resistance to specific chemotherapies.
  • This research uncovers novel mechanisms linking cellular stress responses to drug resistance, offering potential therapeutic targets.

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