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Glucose deprivation induced gene expression

ABSTRACT: Glucose is the main substrates of cancer cell metabolism. Relying on glucose for rapid proliferation and maintaining intracellular redox homeostasis is one of the hallmarkers of cancer cells. During physiology or cancer treatment, cancer cells will face a limited supply of glucose. In these case, cancer cells will undergo cell death . The plasticity of cancer cells is the main factor that allows cancer cells to survive this difficult situation. So in order to better understand the cplasticity of cancer cells, we use glucose-free medium to treat the colorectal cancer cell line HCT116, and perform RNA-Seq analysis on the treated samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159351 | GEO | 2021/05/01

REPOSITORIES: GEO

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Project description:Background: cancer cells rely on glycolysis as main ATP source (Warbürg effect). Tumor-initiating cells (TICs) are the fraction of cells that give raise and repopulate tumors. TICs are exposed to prolonged periods of oxygen and glucose deprivation (OGD), as they live in a hypoxic niche and they withstand prolonged lack of blood vessels during initial tumorigenesis or metastasis formation (avascular phase). Warbürg effect is energetically inefficient; we hypothesize that TICs might have differential metabolic features. Tumor eradication requires killing TICS; finding such features would have therapeutic implications. Methodology/principal findings: 106 MDA-MB-231 breast-cancer cells (hereafter Wt) were exposed for 5 weeks to 0.2% oxygen and 0.1g/l glucose, recovering 9 clones. Both flow-cytometry (50-fold enrichment in the CD24-/CD44+/CD133+ population) and xenografts in NOD/SCID mice using 100 cells (75% vs. 16% engraftment) suggest that OGD-resistant clones are true TICs (hereafter “TIC clones”). TIC clones showed a 30-fold higher replication and viability (BRDU incorporation, colony assay) than Wt. When exposed to OGD, ATP-production dropped 5-fold in WT, but was maintained in TIC clones by increasing 5-fold the fatty acid and oxygen consumption. These properties were explained by lack of upregulation of HIF-1 alpha and PDK1, as well as an increase in ATP-synthase. Analysis with metabolic inhibitors (2-deoxyglucose, antimycin-A) confirmed glycolysis and mitochondrial respiration as main routes of metabolism for Wt and TIC clones respectively. Metabolomics revealed that glutamine catabolism generated the NADPH required to quench reactive oxygen species generated during mitochondrial respiration in TIC clones. Glutamine deprivation or mitochondrial blockers were able to abrogate the viability of TIC clones. Conclusions/significance: the TIC-fraction of a cancer cell population withstands prolonged OGD by switching from the Warbürg effect to mitochondrial respiration. Targeting this metabolic feature abrogates the survival of TICs.

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Glucose deprivation induced gene expression

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