Dataset Information

System Xc- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma

ABSTRACT:

OBJECTIVE: Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc-, a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc- and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC).

METHODS: qPCR and Western blotting were performed to detect changes in xCT and CD98 expression after glucose withdrawal. Then, the cell viability of OSCCs under the indicated conditions was measured. To identify the GD-responsible transcriptional factors of SLC7A11, we performed a luciferase reporter assay and a ChIP assay. Further, metabolomics was conducted to identify changes in metabolites. Finally, mitochondrial function and ATP production were evaluated using the seahorse assay, and NADP+/NADPH dynamics were measured using a NADP+/NADPH kit.

RESULTS: In OSCCs, system Xc- promoted GD-induced cell death by increasing glutamate consumption, which promoted NADPH exhaustion and TCA blockade. Moreover, GD-induced xCT upregulation was governed by the p-eIF2α/ATF4 axis.

CONCLUSIONS: System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.

INSTRUMENT(S): Gas Chromatography MS - positive

SUBMITTER: Miao Wang

PROVIDER: MTBLS5358 | MetaboLights | 2024-01-16

REPOSITORIES: MetaboLights

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Dataset's files

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			Action	DRS
	MTBLS5358	Other
	FILES	Other
	a_MTBLS5358_GC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS5358_GC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular

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Publications

System Xc<sup>-</sup> exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma.

Wang Miao M Li Bo B Meng Wanrong W Chen Yafei Y Liu Hanghang H Zhang Zhuoyuan Z Li Longjiang L

Oral diseases 20231019 5

<h4>Objective</h4>Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc<sup>-</sup>, a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc<sup>-</sup> and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC).<h4>Methods</h4>qPCR and Western blotting were performed to detect changes in xCT and CD9 ...[more]

PMID: 37856618

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Project description:Resistance of Saccharomyces cerevisiae to high furfural concentration is based on NADPH-dependent reduction by at least two oxireductases. Biofuels derived from lignocellulosic biomass hold promises for a sustainable fuel economy, but several problems hamper their economical feasibility. One important problem is the presence of toxic compounds in processed lignocellulosic hydrolysates with furfural as a key toxin. While Saccharomyces cerevisiae has some intrinsic ability to reduce furfural to the less toxic furfuryl alcohol, higher resistance is necessary for process conditions. By comparing an evolved, furfural resistant strain and its parent in micro-aerobic, glucose-limited chemostats at increasing furfural challenge, we elucidate key mechanism and the molecular basis of both natural and high-level furfural resistance. At lower furfural concentrations, NADH-dependent oxireductases are the main defence mechanism. At concentrations above 15 mM, however, [1-13C]-flux and global array-based transcript analysis demonstrated that the NADPH-generating flux through pentose-phosphate pathway increases and that NADPH-dependent oxireductases became the major resistance mechanism. The transcript analysis further revealed that iron transmembrane transport is up-regulated in response to furfural. While these responses occur in both strains, high-level resistance in the evolved strain was based on strong induction of ADH7, the uncharacterised ORF YKL071W and 4 further, likely NADPH-dependent oxireductases. By overexpressing the ADH7 gene and the ORF YKL071W, we inverse engineered significantly increased furfural resistance in the parent strain, thereby demonstrating these two enzymes to be key elements of the resistance phenotype. Experiment Overall Design: RNA levels were measured in glucose limited, micro-aerobic chemostat cultures with different concentrations of the growth inhibitor furfural. Two strains were compared: TMB3400-FT30-3 is a strain that has been evolutionary adapted to withstand high furfural concentrations. TMB3400 is its less resistant parent. Number of biological replicates: 2-3.

Dataset Information

System Xc- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma

CONCLUSIONS: System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.

Dataset's files

Publications

System Xc<sup>-</sup> exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

System Xc- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma

CONCLUSIONS: System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.

Dataset's files

Publications

System Xc&lt;sup&gt;-&lt;/sup&gt; exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

System Xc<sup>-</sup> exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma.