Ferroptosis-activating metabolite acrolein antagonizes necroptosis and anti-cancer therapeutics
Hyun W. Bae, Seonghyun Moon, Mengmeng Chang, Fenfen Zhang, Yeonseo Jang, Wonyoung Kim, Soyeon Kim, Minjie Fu, Jae‐Min Lim, Seongjun Park, Chirag Patel, Raghvendra Mall, Min Zheng, Si Ming Man, Rajendra Karki
Abstract
Dysregulated cell death leading to uncontrolled cell proliferation is a hallmark of cancer. Chemotherapy-induced cell death is critical for the success of cancer treatment but this process is impaired by metabolic byproducts. How these byproducts interfere with anti-cancer therapy is unclear. Here, we show that the metabolic byproduct acrolein derived from polyamines, tobacco smoke or fuel combustion, induces ferroptosis independently of ZBP1, while suppressing necroptosis in cancer cells by inhibiting the oligomerization of the necroptosis effector MLKL. Loss of the enzyme SAT1, which contributes to intracellular acrolein production, sensitizes cells to necroptosis. In mice, administration of an acrolein-trapping agent relieves necroptosis blockade and enhances the anti-tumor efficacy of the chemotherapeutic drug cyclophosphamide. Human patients with cancer coupled with a higher cell death activity but a lower expression of genes controlling polyamine metabolism exhibit improved survival. These findings highlight that the removal of metabolic byproducts improves the success of certain chemotherapies. Acrolein, a byproduct of polyamine metabolism and chemotherapeutic agents, is also found in cigarette smoke. Here the authors report that acrolein mediates spermine-induced ferroptosis, while in ferroptosis-resistant cancer cells, acrolein suppresses necroptosis by inhibiting the oligomerization of MLKL, contributing to chemotherapy resistance.