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Overexpression of SLC2A1, ALDOC and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids.

ABSTRACT: The three-dimensional (3D) tumor spheroid model exhibits enhanced fidelity in replicating the tumor microenvironment and demonstrates exceptional resistance to clinical drugs compared to the two-dimensional (2D) monolayer model. In this study, we used multi-omics (transcriptome, proteomics, and metabolomics) tools to explore the molecular mechanisms and metabolic differences of the two culture models. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways revealed that the differentially expressed genes between the two culture models were mainly enriched in cellular components and biological processes associated with extracellular matrix, extracellular structural organization and mitochondrial function. A combined analysis of three omics data revealed 11 possible drug resistance targets. Among these targets, 7 genes, AKR1B1, ALDOC, GFPT2, GYS1, LAMB2, PFKFB4 and SLC2A1, exhibited significantly up-regulation. Conversely, 4 genes, COA7, DLD, IFNGR1 and QRSL1, were significantly down_x0002_regulated. Clinical prognostic analysis using the TCGAsurvival database indicated that high expression groups of SLC2A1, ALDOC and PFKFB4 exhibited a significant negative correlation with patient survival. We further validated their involvement in chemotherapy drug resistance, indicating their potential significance in improving prognosis and chemotherapy outcomes. These results provide valuable insights into potential therapeutic targets that can potentially enhance treatment efficacy and patient outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270612 | GEO | 2025/06/22

REPOSITORIES: GEO

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Overexpression of SLC2A1, ALDOC and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids

Project description:The three-dimensional (3D) tumor spheroid model exhibits enhanced fidelity in replicating the tumor microenvironment and demonstrates exceptional resistance to clinical drugs compared to the two-dimensional (2D) monolayer model. In this study, we used multi-omics (transcriptome, proteomics, and metabolomics) tools to explore the molecular mechanisms and metabolic differences of the two culture models. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways revealed that the differentially expressed genes between the two culture models were mainly enriched in cellular components and biological processes associated with extracellular matrix, extracellular structural organization and mitochondrial function. A combined analysis of three omics data revealed 11 possible drug resistance targets. Among these targets, 7 genes, AKR1B1, ALDOC, GFPT2, GYS1, LAMB2, PFKFB4 and SLC2A1, exhibited significantly up-regulation. Conversely, 4 genes, COA7, DLD, IFNGR1 and QRSL1, were significantly down regulated. Clinical prognostic analysis using the TCGAsurvival database indicated that high expression groups of SLC2A1, ALDOC and PFKFB4 exhibited a significant negative correlation with patient survival. We further validated their involvement in chemotherapy drug resistance, indicating their potential significance in improving prognosis and chemotherapy outcomes. These results provide valuable insights into potential therapeutic targets that can potentially enhance treatment efficacy and patient outcomes.

2024-06-12 | PXD053058 |

Overexpression of SLC2A1, ALDOC and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids.

Project description:Overexpression of SLC2A1, ALDOC and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids.

| PRJNA1127566 | ENA

The biological function of GYS1 and p53 in ovarian clear cell carcinoma cell line.

Project description:Ovarian cancer (OC) is a highly fatal and refractory malignancy affecting women, with platinum resistance remaining a major clinical dilemma. Ovarian clear cell carcinoma (OCCC) frequently exhibits increased platinum refractoriness than the other OC subtypes, accompanied by heightened glycogen that engenders clear-cell morphology and wild-type p53. However, their roles in platinum resistance are unclear. Here, we investigated whether glycogen promotes OCCC platinum resistance, and found that GYS1 as a rate-limiting enzyme in glycogen synthesis is clinically associated with poor prognosis and chemoresistance in OCCC. GYS1 is a rate-limiting enzyme in glycogen synthesis, which is clinically associated with poor prognosis and chemoresistance in OCCC. Mechanistically, p53 promotes GYS1 breakdown via upregulating RNF144a, while GYS1 enhances reversed ubiquitination and degradation toward p53 by competitively bound to the USP14, forming a positive feedback circuit. Under platinum stress the accumulated glycogen is mobilized by p53/GYS1 feedback circuit, which fueling energetic NADPH production, hence gaining disulfidptosis invulnerability and increased platinum resistance in OCCC. Collectively, our study identifies glycogen as a contributor to OCCC platinum resistance and elucidates the underlying mechanisms, highlighting a crucial p53/GYS1 positive feedback loop.

2025-09-17 | GSE281988 | GEO

Discovery of inhibitors of the HSP90-Calcineurin-NFAT pathway against glioblastoma

Project description:We report the application of mRNA sequencing technology for high-throughput profiling of genes expression changes in U87 glioblastoma cells after treatment with compound YZ129 that we identified in our screen. By analyzing the total mRNA sequencing between YZ129 treatment group and the DMSO control group, we identified that 181 genes were significantly downregulated (changed >2 folds), while 226 genes were significantly upregulated (changed >2 folds). The downregulated genes were mainly associated with hypoxia (ALDOC, TMEM45A, F3, FOS, GFBP1, etc), glycolysis (SLC2A1, ANGPTL4, ENO2, LDHA, PGM, PFKFB3, etc.), PI3K/AKT/mTOR pathway (AK4, SLC2A1, PDK1, PGM1, PLOD2, TUBA4A, etc.), EMT (epithelial-mesenchymal transition) (VEGFA, ID2, COL1A1, FOXC2, LOXL2, etc.), G2/M checkpoint (UBE2C, FBXO5 (Emi1), TOP2A, MCM5/6), etc. some of the upregualted genes may contribute to the possible chemoresistance, such as FOSB, INHBA, EDN1, IRS2, KDM6B. This study yields a global view on molecular response to YZ29 treatment in GBM cells at mRNA level.

2018-10-01 | GSE108749 | GEO

Glycolysis enzyme PFKFB4 enhances HIF1a transcriptional activity by blocking the ubiquitin E3 ligase FBXO28 in glioblastoma

Project description:Glioblastoma is one of the most aggressive primary brain tumours in adults, with a dismal median overall survival of only 14 months after diagnosis1,2. Glioblastoma stem-like cells (GSCs), are particularly resistant to current therapies3,4, capable of self-renewal and tumour initiation5,6 and are hence thought to be major contributors to patient relapse. Glycolysis gene 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is an essential gene for GSC survival, and is upregulated in these cells compared with in normal brain7. However, the mode of action of PFKFB4 in GSCs is unknown. Here we show a new role for PFKFB4 in the regulation of Hypoxia Inducible Factor 1 alpha (HIF1α) in GSCs. In a metabolic tracing study, we found that silencing PFKFB4 in GSCs resulted in a global downregulation of glucose metabolism. Gene expression profiling of PFKFB4-silenced GSCs revealed a downregulation of HIF1α target genes, and HIF1α protein levels are dramatically reduced in PFKFB4-silenced GSCs and other cancer cell lines. Finally, through mass spectrometric analysis of immunoprecipitated PFKFB4, we identified the ubiquitin E3 ligase, F box only protein 28 (FBXO28), as a new interaction partner of PFKFB4, which we show to regulate ubiquitylation and subsequent proteasomal degradation of HIF1α. Crucially, this newly discovered function of PFKFB4, coupled with its cancer specificity, provides a new strategy for inhibiting HIF1α in a cancer specific manner. Compounds which disrupt the interaction between PFKFB4 and FBXO28 could be interesting therapeutic agents against glioblastoma and other cancer entities in which PFKFB4 regulates HIF1α stability.

2022-10-13 | PXD009807 | Pride

Effects of PFKFB4 deletion on transcriptional reprogramming in breast cancer cells

Project description:To explore the mechanisms by which PFKFB4 promotes breast cancer metastasis, we CRISPR-Cas knock-out PFKFB4 in two breast cancer lines for RNA-seq to identify downstream target genes that are regulated by PFKFB4

2022-12-31 | GSE217132 | GEO

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells

Project description:The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 down-regulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53 deficient cancer cells increased levels of the allosteric regulator fructose 2,6-bisphophate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53 deficient cancer cells. Moreover, depletion of PFKFB4 attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4 induced apoptosis in p53 deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment.

2017-04-03 | GSE89110 | GEO

Bulk RNA-seq of siGFPT2 and NC grouped H1975 cells

Project description:In the evolving field of cancer immunotherapy, EGFR-mutated NSCLC presents a significant challenge, demonstrating marked resistance to established treatments. An effective method to counter this resistance remains elusive. Through comprehensive genetic and pharmacological analyses across various models, we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a key facilitator of immune evasion in EGFR-mutated NSCLC.

2024-06-10 | GSE269440 | GEO

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| 2349788 | ecrin-mdr-crc

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