ArticleJournal of experimental & clinical cancer research : CR2021
PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 84 citations in OpenAlex.
- Research progress in metabolic reprogramming and targeting metabolic pathways for clear cell renal cell carcinoma.Genes & diseases · 2026Review
- WDR12 Promotes Glucose Metabolism via PFKFB4 Upregulation in Gastric Cancer.Cancer science · 2026Article
- Metabolic Regulation of Immune Responses: Molecular Mechanisms, Diseases, and Therapeutic Targets.MedComm · 2026Review
- Acute glucose stimulation drives coordinated translational reprogramming in primary pancreatic islets: from global remodeling to fine-tuned insulin synthesis.Frontiers in endocrinology · 2026Article
- Obesity-driven metabolic reprogramming and immune dysfunction in renal cancer.Frontiers in immunology · 2026Review
- Targeting phosphofructokinase in cancer: integrating natural products for metabolic reprogramming and therapeutic innovation.Frontiers in pharmacology · 2026Review
- Mitochondrial energy metabolism genes as prognostic biomarkers in clear cell renal cell carcinoma via single-cell and bulk RNA sequencing analyses.Discover oncology · 2025Article
- Targeting phosphofructokinase 2 the isoform PFKFB4 suppresses glioblastoma proliferation and malignancy.Genes & genomics · 2025Article
- PGLS as an immune and prognostic biomarker: from pan-cancer analysis to validation.Discover oncology · 2025Article
- Lysine acetylation and its role in the pathophysiology of acute pancreatitis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Review
- Emerging roles of metabolic biomarkers in renal cell carcinoma: from molecular mechanisms to clinical implications.Frontiers in cell and developmental biology · 2025Review
- Review
- Decoding sunitinib resistance in ccRCC: Metabolic-reprogramming-induced ABAT and GABAergic system shifts.iScience · 2024Article
- mir-605-3p prevents liver premetastatic niche formation by inhibiting angiogenesis via decreasing exosomal nos3 release in gastric cancer.Cancer cell international · 2024Article
- Multi-omics and immunogenomics analysis revealed PFKFB3 as a targetable hallmark and mediates sunitinib resistance in papillary renal cell carcinoma: in silico study with laboratory verification.European journal of medical research · 2024Article
- Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer.Acta pharmaceutica Sinica. B · 2024Review
- Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics.Journal of translational medicine · 2024Article
- Comparative clinical significance and biological roles of PFKFB family members in oral squamous cell carcinoma.Cancer cell international · 2023Article
- ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis.Journal of experimental & clinical cancer research : CR · 2023Article
- Endoplasmic Reticulum Stress in Renal Cell Carcinoma.International journal of molecular sciences · 2023Review
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundKinases play critical role in clear-cell renal cell carcinoma (ccRCC). We aim to exploit novel kinase that is both protumorigenic and drugable in ccRCC.
methodsReproduction of public datasets with validation using microarray was performed to identify candidate gene. Functionality was studied using multi-omics with validation in vitro and in vivo.
results6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) was differentially expressed showing significantly higher expression in tumor than in normal kidney. PFKFB4 overexpression was associated with advanced tumor grade, stage and worsened prognosis. PFKFB4-knockdown significantly impaired fitness in cell proliferation, migration and wound healing. Despite being recurrently deleted on 3p, PFKFN4 mRNA remained actively transcribed by HIF1α. Metabolomics showed overexpressed PFKFB4 showed enriched metabolites in pentose phosphate pathway (PPP). Phosphoproteomics and immunoprecipitation showed PFKFB4 also phosphorylated NCOA3 which interacted with FBP1 to counteract overactive PPP flux, forming a regulatory loop. PFKFB4-knockdown overcame resistance to Sunitinib in vitro and in vivo both in xenograft and tail-vein injection murine models.
conclusionWe concluded PFKFB4 was associated with PPP activity and the fine-tuning of which was mediated by its phosphorylation of NCOA3. Targeting PFKFB4 held promise to combat resistance to Sunitinib.
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