Glutamine Synthetase Shields Triple-negative Breast Cancer Cells from Ferroptosis in Metastasis Triggered by Glutamine Deprivation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Zhaoting Yang
PROVIDER: PXD065305 | iProX | Mon Jun 23 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:There are two major subtype of cells in breast cancer. These cancer cells response differently to glutamine deprivation, here we use one luminal type of breast cancer cell (MCF7) and one basal type of breast cancer cell (MDAMB231) to compare the gene expression differences of these two types of cancer cells in glutamine deprivation. Many cancer cells depend on glutamine for survival and oncogenic transformation. Although targeting glutamine metabolism is proposed as novel therapies, their heterogeneity among different tumors is unknown. Here, we found only basal-type, but not luminal-type breast cancer cells, exhibited phenotypes of glutamine dependency and may benefit from glutamine-targeting therapeutics. The glutamine independence of luminal-type cells is caused by the specific expression of glutamine synthetase (GS), a pattern recapitulated in luminal breast cancers. The co-culture of luminal cells partially rescued the basal cells under glutamine deprivation, suggesting glutamine symbiosis. The luminal-specific expression of GS is directly induced GATA3 and down-regulates glutaminase expression to maintain subtype-specific glutamine metabolism. Collectively, these data indicate the distinct glutamine phenotypes among breast cells and enable the rational design of glutamine targeted therapies. Gene expression analysis in MCF7 and MDAMB231 cultured with or without glutamine for 24h
2012-01-01 | E-GEOD-26370 | biostudies-arrayexpress
Project description:There are two major subtype of cells in breast cancer. These cancer cells response differently to glutamine deprivation, here we use one luminal type of breast cancer cell (MCF7) and one basal type of breast cancer cell (MDAMB231) to compare the gene expression differences of these two types of cancer cells in glutamine deprivation. Many cancer cells depend on glutamine for survival and oncogenic transformation. Although targeting glutamine metabolism is proposed as novel therapies, their heterogeneity among different tumors is unknown. Here, we found only basal-type, but not luminal-type breast cancer cells, exhibited phenotypes of glutamine dependency and may benefit from glutamine-targeting therapeutics. The glutamine independence of luminal-type cells is caused by the specific expression of glutamine synthetase (GS), a pattern recapitulated in luminal breast cancers. The co-culture of luminal cells partially rescued the basal cells under glutamine deprivation, suggesting glutamine symbiosis. The luminal-specific expression of GS is directly induced GATA3 and down-regulates glutaminase expression to maintain subtype-specific glutamine metabolism. Collectively, these data indicate the distinct glutamine phenotypes among breast cells and enable the rational design of glutamine targeted therapies.
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Project description:To understand the effects of glutamine deprivation on cell physiology we performed global analysis of gene expression in response to glutamine deprivation. U2OS cells were subjected to glutamine deprivation for 24h followed by RNA extraction and microarray analysis.
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Project description:To understand the effects of glutamine deprivation on cell physiology we performed global analysis of gene expression in response to glutamine deprivation. U2OS cells were subjected to glutamine deprivation for 24h followed by RNA extraction and microarray analysis. U2OS cells were plated overnight followed by treatment for 24h with glutamine-containing and glutamine-depleted media. Three biological replicates were assayed for each condition.
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Project description:We applied the quantitative proteomics approach to estimate the relative abundance of proteins in HepG2 cells treated by glutamine deprivation. Two independent cultured cell lysates, namely control and glutamine deprivation, were marked with iTRAQ labels and subjected to LC-ESI-MS/MS analysis. The tryptic peptides of two samples were labeled with mass 113 (control) and 119 (glutamine deprivation) isobaric iTRAQ tags.
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Project description:Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a high risk of recurrence following treatment. Inhibition of cysteine uptake by erastin effectively induces mesenchymal TNBC undergoing prompt ferroptosis. However, a small residual population of cancer cells keeps resistant and survived during the erastin treatments, which might mimic tumor relapse in patients after therapy. We enriched and established the erastin-resistant/recurrent TNBC cell models by multi-cycle challenges of erastin. Identified epigenetic compounds could abolish such resistance in recurrent cells. Intriguingly, recurrent TNBC failed to grow in anchorage-independent conditions, implying a loss of tumorigenicity. By analyzing transcriptomic profiling, recurrent TNBC displayed highly transcriptomic alterations and attenuated signaling processes, including K-Ras signaling. Knockout of CST4, a member of the cystatin gene family strongly suppressed in recurrent cells, significantly reduced the tumorigenic potential and K-Ras signaling. Our findings suggested that targeted cysteine therapy could be a valid treatment for TNBC with a low possibility of tumorigenicity formation.
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