Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45, Gothenburg, Sweden.
Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE413 45, Gothenburg, Sweden.
Nat Commun. 2023 May 20;14(1):2886. doi: 10.1038/s41467-023-38568-5.
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.
顺铂通过 DNA 损伤杀死增殖细胞，但对肿瘤、肾脏和神经元中的有丝分裂后细胞也有深远影响。然而，顺铂对有丝分裂后细胞的影响仍知之甚少。在模型系统中，秀丽隐杆线虫成虫是唯一具有完全有丝分裂后体组织的物种。p38 MAPK 途径通过 SKN-1/NRF 控制 ROS 解毒，通过 ATF-7/ATF2 控制免疫反应。在这里，我们表明 p38 MAPK 途径突变体对顺铂敏感，尽管顺铂暴露会增加 ROS 水平，但 skn-1 突变体具有抗性。顺铂暴露会导致 PMK-1/MAPK 和 ATF-7 的磷酸化，IRE-1/TRF-1 信号模块在上游发挥作用 p38 MAPK 途径激活信号。我们确定了响应蛋白，其丰度的增加取决于 IRE-1/p38 MAPK 活性以及顺铂暴露。这四种蛋白质对于免受顺铂毒性至关重要，顺铂毒性的特征是坏死性死亡。我们得出结论，p38 MAPK 途径驱动的蛋白质对于成虫对顺铂的抵抗力至关重要。
