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Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans

Author

Listed:
  • Dorota Raj

    (University of Gothenburg)

  • Bashar Kraish

    (University of Gothenburg)

  • Jari Martikainen

    (University of Gothenburg, Gothenburg)

  • Agnieszka Podraza-Farhanieh

    (University of Gothenburg
    University of Gothenburg)

  • Gautam Kao

    (University of Gothenburg)

  • Peter Naredi

    (University of Gothenburg
    Sahlgrenska University Hospital)

Abstract

Cisplatin kills proliferating cells via DNA damage but also has profound effects on post-mitotic cells in tumors, kidneys, and neurons. However, the effects of cisplatin on post-mitotic cells are still poorly understood. Among model systems, C. elegans adults are unique in having completely post-mitotic somatic tissues. The p38 MAPK pathway controls ROS detoxification via SKN-1/NRF and immune responses via ATF-7/ATF2. Here, we show that p38 MAPK pathway mutants are sensitive to cisplatin, but while cisplatin exposure increases ROS levels, skn-1 mutants are resistant. Cisplatin exposure leads to phosphorylation of PMK-1/MAPK and ATF-7 and the IRE-1/TRF-1 signaling module functions upstream of the p38 MAPK pathway to activate signaling. We identify the response proteins whose increased abundance depends on IRE-1/p38 MAPK activity as well as cisplatin exposure. Four of these proteins are necessary for protection from cisplatin toxicity, which is characterized by necrotic death. We conclude that the p38 MAPK pathway-driven proteins are crucial for adult cisplatin resilience.

Suggested Citation

  • Dorota Raj & Bashar Kraish & Jari Martikainen & Agnieszka Podraza-Farhanieh & Gautam Kao & Peter Naredi, 2023. "Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38568-5
    DOI: 10.1038/s41467-023-38568-5
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