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

Source:

			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:Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of PFKP (phosphofructokinase, platelet), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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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.