The molecular basis of targeting PFKFB3 as a therapeutic strategy against cancer

Luo, Lu; Chen, Yaoyu; Zhu, Yushan

doi:10.18632/oncotarget.19513

Cited by 63 publications

(61 citation statements)

References 51 publications

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“…PFKFB3 is a potent regulator of glycolysis and is frequently upregulated in cancers [ 167 ]. Various inhibitors of PFKFB3 have been reported, including the weak PFKFB3 inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).…”

Section: Therapeutic Opportunities Targeting Altered Ccmmentioning

confidence: 99%

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Kong

et al. 2020

Molecules

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Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

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Section: Therapeutic Opportunities Targeting Altered Ccmmentioning

confidence: 99%

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Kong

et al. 2020

Molecules

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“…In hypoxia, in the absence of HIF1a, we found a blockage at the metabolic step mediated by fructose-bisphosphate aldolase (Aldolase A, ALDOA), catabolizing the cleavage of Fru-1,6BP to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Previously, it has been shown that PFKB3 was key in regulating glycolysis one step earlier, and has been the focus of several approaches to develop inhibitors (31).…”

Section: Discussionmentioning

confidence: 99%

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism

Valli

Morotti

Zois

et al. 2019

Molecular Cancer Research

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Hypoxia-inducible factor 1a is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1a is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1a, using the HCT116 colon cancer cell line with deleted HIF1a versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1a, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth.Implications: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting. Analysis of the HCT116 hypoxic metabolic phenotype. A-C, Metabolomics-and proteomics-integrated circos-plots showing significantly regulated features only in KON versus WTN, WTH versus WTN, KOH versus KON, and KOH versus WTH (upper side circos-plots). Adjusted P < 0.05 ( Ã ) or P < 0.01 ( ÃÃ ) are indicated for the different experimental comparisons (connecting lines inside circos-plots): KON/WTN (gray/white-gray connection) WTH/WTN (gold/white-brown connection), KOH/KON (blue/gray-violet connection), KOH/WTH (blue/gold-green connection). Colored boxes (lower side circos-plots linked to connecting lines) represent different metabolic pathways, while colored boxes (inside circos-plots linked to connecting lines) identify the biological condition where the feature is upregulated. D, Heatmap of integrated transomics (proteomics and transcriptomics); mRNA and protein log 2 FC are calculated for WTH-WTN and KOH-WTH. Feature selection was based on departure from 95% confidence intervals of the linear model distribution built for each comparison (WTH-WTN and KOH-WTH). Metabolic pathways: glycogen (GLG), glycolysis (GLY), Krebs cycle (TCA), adenosine triphosphate (ATP), creatine (Cr), oxidation-reduction (REDOX), and adenosyl metabolism (ADE). E, Targeted metabolomics showing distribution of ATP, ADP, AMP, ATP/AMP, and ATP/ADP ratios in WTN, KON, WTH, and KOH cell after 24 hours in 21% and 1% O 2 . Raw intensities and ratios are shown as 0-1 normalized levels' rela...

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“…PFKFB3 inhibitors reduce anaerobic glycolysis by blocking the 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 enzyme. This protein is highly expressed by tumour cells, explaining the interest of PFKB3 inhibitors for cancer therapy ( Lu et al, 2017 ), but also in endothelial cells. Indeed, inhibition of PFKB3 reduces endothelial cell proliferation and angiogenesis ( Cantelmo et al, 2016 ; Schoors et al, 2014 ), but plays also an anti-inflammatory effect by limiting NLRP3 activation ( Finucane et al, 2019 ).…”

Section: Concluding Remarks: Therapeutic Opportunitiesmentioning

confidence: 99%

Metabolic adaptations of cells at the vascular-immune interface during atherosclerosis

Bonacina

Dalt

Catapano

et al. 2021

Molecular Aspects of Medicine

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Metabolic reprogramming is a physiological cellular adaptation to intracellular and extracellular stimuli that couples to cell polarization and function in multiple cellular subsets. Pathological conditions associated to nutrients overload, such as dyslipidaemia, may disturb cellular metabolic homeostasis and, in turn, affect cellular response and activation, thus contributing to disease progression. At the vascular/immune interface, the site of atherosclerotic plaque development, many of these changes occur. Here, an intimate interaction between endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and immune cells, mainly monocytes/macrophages and lymphocytes, dictates physiological versus pathological response. Furthermore, atherogenic stimuli trigger metabolic adaptations both at systemic and cellular level that affect the EC layer barrier integrity, VSMC proliferation and migration, monocyte infiltration, macrophage polarization, lymphocyte T and B activation. Rewiring cellular metabolism by repurposing “metabolic drugs” might represent a pharmacological approach to modulate cell activation at the vascular immune interface thus contributing to control the immunometabolic response in the context of cardiovascular diseases.

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The molecular basis of targeting PFKFB3 as a therapeutic strategy against cancer

Cited by 63 publications

References 51 publications

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism

Metabolic adaptations of cells at the vascular-immune interface during atherosclerosis

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