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Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism
Open accessAbstract
The increased glucose metabolism in cancer cells is required to fulfill their high energetic and biosynthetic demands. Changes in the metabolic activity of cancer cells are caused by the activation of oncogenes or loss of tumor suppressors. They can also be part of the metabolic adaptations to the conditions imposed by the tumor microenvironment, such as the hypoxia response. Among the metabolic enzymes that are modulated by these factors are the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases (PFKFBs), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate (Fru-2,6-P2). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating the rate-limiting enzyme of glycolysis phosphofructokinase-1 (PFK-1). Therapeutic strategies designed to alter the levels of this metabolite are likely to interfere with the metabolic balance of cancer cells, and could lead to a reduction in cancer cell proliferation, invasiveness and survival. This article will review our current understanding of the role of PFKFB proteins in the control of cancer metabolism and discuss the emerging interest in these enzymes as potential targets for the development of antineoplastic agents.
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![Figure 2 Relative activity of 6-phosphofructo-2-kinase (PFK-2)/fructose 1,6-bisphosphatase (FBPase-2). Properties of the PFK-2/FBPase-2 enzymes. Information on chromosomal location and relative enzymatic activity of the different isoforms has been taken from Okar et al. Trends BiochemSci (2001) [7].](/paper-figures/5f2e50d99f0044eb8db89f887c0062fc/balancing-glycolytic-flux-the-role-of-6-phosphofructo-2-kinase-fructose-2-6-figure-2.jpg)
![Figure 3 Domain organizations and phosphorylation of 6-phosphofructo-2-kinase (PFK-2)/fructose 1,6-bisphosphatase (FBPase-2) isoenzymes. The N-terminal PFK-2 domain is shown in red, the C-terminal FBPase-2 domain is shown in blue and the regulatory domains are shown in green. Phosphorylation sites and the kinases responsible of their phosphorylation are indicated on each main isoforms. The domain structure of human PFK-2/FBPase-2 enzymes is based on Rider et al. Biochem J (2014) [10].](/paper-figures/e22d1ed625cd4760b9368b71b93ebc59/balancing-glycolytic-flux-the-role-of-6-phosphofructo-2-kinase-fructose-2-6-figure-3.jpg)
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“The PFK-2/FBPase-2 family comprises several enzyme isoforms, PFKFB1, PFKFB2, PFKFB3 and PFKFB4, all of which are induced by HIF-1 under hypoxic conditions [101].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [101]
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Cites
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Targeting HIF-1 for cancer therapy
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“Adaptation to hypoxic conditions is largely mediated by HIF, a transcription factor that regulates a distinct transcriptional program [40].”
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TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis
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Deregulation of Glucose Transporter 1 and Glycolytic Gene Expression by c-Myc
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Cited by
Sorted by citations
Metformin—mode of action and clinical implications for diabetes and cancer
Pernicova, I., & Korbonits, M. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.256 · Cited by 1,393
Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?
Hay, N. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.77 · Cited by 1,152
Tumor glycolysis, an essential sweet tooth of tumor cells
Paul, S., Ghosh, S., & Kumar, S. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.09.007 · Cited by 449
Four Key Steps Control Glycolytic Flux in Mammalian Cells
Tanner, L. B., Goglia, A. G., Wei, M. H., Sehgal, T., Parsons, L. R., Park, J. O., White, E., Toettcher, J. E., & Rabinowitz, J. D. (2018) · Cell Systems · doi:10.1016/j.cels.2018.06.003 · Cited by 383
Endothelial PFKFB3 Plays a Critical Role in Angiogenesis
Xu, Y., An, X., Guo, X., Habtetsion, T. G., Wang, Y., Xu, X., Kandala, S., Li, Q., Li, H., Zhang, C., et al. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.303041 · Cited by 256
Metadata
- Authors
- Ros, S., & Schulze, A.
- Affiliations
- Cancer Research UK (GB)
- Corresponding author
- Schulze, Almut
- ORCID
- Schulze, Almut
- Venue
- Cancer & Metabolism
- Published
- 2013-02-04
- Volume
- 1
- Issue
- 1
- Pages
- 8-8
- ISSN
- 2049-3002 (ISSN-L)
- PMC
- PMC4178209
- OpenAlex
- W2106223802
- Cited by
- 269
- References
- 69
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 29 · 2023: 32 · 2022: 31 · 2021: 26 · 2020: 15 · 2019: 20 · 2018: 17 · 2017: 17 · 2016: 19 · 2015: 20 · 2014: 11 · 2013: 2
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer & Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, fructose-2,6-bisphosphate, glycolytic flux, tumor microenvironment, hypoxia response, oncogene activation, tumor suppressor loss
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