脂质过氧化
TLR2型
癌细胞
磷脂
化学
癌症研究
细胞生物学
巨噬细胞
癌症
生物
生物化学
信号转导
氧化应激
TLR4型
膜
遗传学
体外
作者
Rong‐Rong He,Xiang Luo,Zi-Chun Li,Dongdong Li,Zixuan Li,Haibiao Gong,Chang-Yu Yan,Rui‐Ting Huang,Yue Feng,Shurui Chen,Yun‐Feng Cao,Mingxian Liu,Rong Wang,Feng Huang,Wanyang Sun,Hiroshi Kurihara,Wen‐Jun Duan,Lei Liang,Wen Jin,Yifang Li,Yanping Wu
出处
期刊:Research Square - Research Square
日期:2023-10-19
标识
DOI:10.21203/rs.3.rs-3396037/v1
摘要
Abstract Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not well cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic prowess during treatment of tumors with ferroptotic agents is still unknown. Here, we determined that phospholipid peroxidation in macrophages impaired their ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, this discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.
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