ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells

Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anticancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2023-05, Vol.83 (10), p.1646-1665
Main Authors: Hu, Qiangsheng, Dai, Jie, Zhang, Zheng, Yu, Huansha, Zhang, Jing, Zhu, Xinsheng, Qin, Yi, Zhang, Lele, Zhang, Peng
Format: Article
Language:English
Subjects:
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Citric Acid Cycle
Ferroptosis
Glutamine - metabolism
Humans
Lung Neoplasms
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Summary:Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anticancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non-small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo. Metabolomics analysis with stable isotope-labeled glutamine showed that ASS1 promotes reductive carboxylation of cytosolic glutamine and compromises the oxidative tricarboxylic acid cycle from glutamine anaplerosis, reducing mitochondrial-derived lipid reactive oxygen species. Moreover, transcriptome sequencing showed that ASS1 activates the mTORC1-SREBP1-SCD5 axis to promote de novo monounsaturated fatty acid synthesis by using acetyl-CoA derived from the glutamine reductive pathway. Treating ASS1-deficient NSCLC cells with erastin combined with arginine deprivation significantly enhanced cell death compared with either treatment alone. Collectively, these results reveal a previously unknown regulatory role of ASS1 in ferroptosis resistance and provide a potential therapeutic target for ASS1-deficient NSCLC. ASS1 promotes reductive carboxylation of glutamine and confers ferroptosis resistance, providing multiple treatment options for ASS1-deficient non-small cell lung cancer.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-22-1999