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 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.

Protective effects of EGCG on acrolein-induced Caenorhabditis elegans and its mechanism of life extension

“…38,39 Specifically, the phosphorylation of SKN-1 is regulated upstream by the activation of components (SEK-1 and PMK-1) of the p38 MAPK pathway in reaction to increased ROS levels. 40 Furthermore, the antioxidant-promoting effects of IIS are reliant on HSF-1. 41 HSF-1 is suggested to work collaboratively with, yet distinctly from, DAF-16 to promote longevity.…”

“…52 Previous studies on C. elegans have shown that SKN-1, activated by sek-1 , nsy-1 and pmk-1 , could synthesize ROS-resistant detoxifying enzymes, thereby assisting in the regulation of DAF-16. 40 Through the lifespan experiments with the 12 mutants, we reported that EGCG did not increase the lifespan of daf-16 , skn-1 , eat-2 , sir-2.1 , hsf-1 , age-1 , jnk-1 , jkk-1 , pmk-1 , sek-1 , aak-2 , and nsy-1 mutants, confirming that the beneficial effects from EGCG were associated with the IIS and MAPK pathways (Fig. 7).…”