Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38568-5 |
| _version_ | 1797822842721533952 |
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| author | Dorota Raj Bashar Kraish Jari Martikainen Agnieszka Podraza-Farhanieh Gautam Kao Peter Naredi |
| author_facet | Dorota Raj Bashar Kraish Jari Martikainen Agnieszka Podraza-Farhanieh Gautam Kao Peter Naredi |
| author_sort | Dorota Raj |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T10:14:03Z |
| format | Article |
| id | doaj.art-e098cb21c00b416897f303d93b9bdcf5 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T10:14:03Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e098cb21c00b416897f303d93b9bdcf52023-05-21T11:20:23ZengNature PortfolioNature Communications2041-17232023-05-0114111810.1038/s41467-023-38568-5Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegansDorota Raj0Bashar Kraish1Jari Martikainen2Agnieszka Podraza-Farhanieh3Gautam Kao4Peter Naredi5Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of GothenburgDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of GothenburgBioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, GothenburgDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of GothenburgDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of GothenburgDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of GothenburgAbstract 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.https://doi.org/10.1038/s41467-023-38568-5 |
| spellingShingle | Dorota Raj Bashar Kraish Jari Martikainen Agnieszka Podraza-Farhanieh Gautam Kao Peter Naredi Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans Nature Communications |
| title | Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans |
| title_full | Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans |
| title_fullStr | Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans |
| title_full_unstemmed | Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans |
| title_short | Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans |
| title_sort | cisplatin toxicity is counteracted by the activation of the p38 atf 7 signaling pathway in post mitotic c elegans |
| url | https://doi.org/10.1038/s41467-023-38568-5 |
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