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Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling

Nat Chem Biol. 2024-05; 
Zhe Li, Zhi-Min Xu, Wei-Peng Chen, Xiao-Jing Du, Chun-Xian Ou, Zi-Kang Luo, Rong Wang, Chu-Qing Zhang, Chao-Dong Ge, Meng Han, Fudi Wang, Rong-Rong He, Wan-Yang Sun, Jun Ma, Xiao-Yu Liang, Zhuo-Wei Liu
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Proteins, Expression, Isolation and Analysis … Total protein was separated by SDS–PAGE (GenScript) and transferred to nitrocellulose filter membranes. The membranes were blocked and incubated with primary antibodies (… Get A Quote

摘要

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679)... More

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