The potential utility of PFKFB3 as a therapeutic target

Bartrons, Ramón; Rodríguez-García, Ana; Simon-Molas, Helga; Castaño, Esther; Manzano, Ànna; Navarro-Sabaté, Àurea

doi:10.1080/14728222.2018.1498082

Cited by 67 publications

(54 citation statements)

References 127 publications

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“…PFKFB3 is a bifunctional enzyme that catalyzes the synthesis and the degradation of fructose‐2,6‐bisphosphate. PFKFB3 is recognized as a key metabolic driver in cancer cells, and the molecule is considered a therapeutic target to inhibit cell proliferation and impair survival . CD4 T cells from healthy individuals upregulate PFKFB3 upon stimulation, with a maximum expression 72 h poststimulation.…”

Section: Ra Cd4 T Cells Shunt Glucose Toward the Pentose Phosphate Pamentioning

confidence: 99%

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Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

114

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In rheumatoid arthritis (RA), breakdown of self‐tolerance and onset of clinical disease are separated in time and space, supporting a multi‐hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease‐specific metabolic signature, which enables naive CD4 T cells to differentiate into pro‐inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N‐myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose‐6‐phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints.

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Section: Ra Cd4 T Cells Shunt Glucose Toward the Pentose Phosphate Pamentioning

confidence: 99%

“…PFKFB3 is recognized as a key metabolic driver in cancer cells, and the molecule is considered a therapeutic target to inhibit cell proliferation and impair survival. 19,20 CD4 T cells from…”

Section: R a CD 4 T Cell S S H Unt G Lucos E Toward The Pentos E Phmentioning

confidence: 99%

Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

114

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“…Among all PFKFBs, PFKFB3 exerts a central role in controlling glycolysis flux and has aroused a great deal of attention in recent years . In addition to activation of mTORC1, inactivated mutation of Pten or the aberrant activation of Ras and PI3K have been shown that take part in the regulation of glycolysis and tumorigenesis through modification of PFKFB3 expression . However, the detailed transcriptional regulation mechanisms of PFKFB3 expression are far from fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…34 In addition to activation of mTORC1, inactivated mutation of Pten or the aberrant activation of Ras and PI3K have been shown that take part in the regulation of glycolysis and tumorigenesis through modification of PFKFB3 expression. 35,36 However, the detailed transcriptional regulation mechanisms of PFKFB3 expression are far from fully understood. Zhu et al demonstrated that the transcription factor PU.1 upregulates PFKFB3 which is responsible for the chemoresistance in chronic myeloid leukemia.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

Wang

Tang

et al. 2020

IUBMB Life

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Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the benign tumor formation in multiple organs. The main etiology of TSC is the loss‐of‐function mutation of TSC1 or TSC2 gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) expression in Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) compared with the control cells. Inhibition of mTORC1 led to a dramatic decrease of PFKFB3 expression, indicating PFKFB3 regulation by mTORC1. Moreover, suppression of mTORC1 inhibited the expression of PFKFB3 in rat uterine leiomyoma‐derived Tsc2‐null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia‐inducible factor 1α (HIF‐1α) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1‐ or Tsc2‐deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1‐ or Tsc2‐null MEFs than treatment with single drug. We conclude that loss of TSC1 or TSC2 led to upregulated expression of PFKFB3 through activation of mTORC1/HIF‐1α signaling pathway and co‐administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1‐related tumors.

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“… 4 The activity of PFK-1 is under the control of F2,6P2, which is generated by the phosphorylation of F6P to fructose-2,6-bisphosphate (F2,6BP). 5 This reaction is catalyzed by enzymes in the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family. One member, PFKFB3, has been shown to be upregulated in various cancers and associated with poor survival in patients with cancer, including breast cancer, gastric cancer, colorectal cancer, and glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

<p>MicroRNA-3666 Suppresses Cell Growth in Head and Neck Squamous Cell Carcinoma Through Inhibition of PFKFB3-Mediated Warburg Effect</p>

Chen¹,

Cao²,

Wu³

et al. 2020

OTT

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Purpose MicroRNA-3666 (miR-3666) is aberrantly expressed and plays critical roles in numerous human tumors. However, the expression pattern, biological role, and mechanisms of action of miR-3666 in head and neck squamous cell carcinoma (HNSCC) remain unknown. Therefore, we attempted to determine the expression status and function of miR-3666 in HNSCC and to explore the underlying mechanisms in detail. Methods In this study, quantitative real-time polymerase chain reaction was carried out to measure the expression of miR-3666 HNSCC tissues. A series of experiments, including a Cell Counting Kit-8 assay, colony formation assay, BrdU incorporation and apoptosis analysis, were applied to test whether miR-3666 affects the growth of HNSCC cells. Glucose uptake and lactate production measurements and extracellular acidification and oxygen consumption rate assays were conducted to determine the effect of miR-3666 on glycolysis. Results We found that miR-3666 showed a decreased expression in HNSCC tissues. Further functional studies demonstrated that miR-3666 inhibited the growth of HNSCC cells by suppressing cell proliferation and promoting apoptosis. Bioinformatics analysis and luciferase reporter assays identified phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), a key enzyme regulating glycolysis, as a direct target of miR-3666. Through inhibition of PFKFB3, miR-3666 decreased glycolysis in HNSCC cells by reducing the production of F2,6BP. Importantly, glycolysis suppression caused by miR-3666 was found to be required for its inhibitory effect on HNSCC cell growth. Conclusion Our data suggest that miR-3666 functions as a tumor suppressor by decreasing the rate of glycolysis through inhibition of PFKFB3 activity, and this miRNA may present a potential candidate for HNSCC therapy.

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The potential utility of PFKFB3 as a therapeutic target

Cited by 67 publications

References 127 publications

Immunometabolism in the development of rheumatoid arthritis

Immunometabolism in the development of rheumatoid arthritis

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

<p>MicroRNA-3666 Suppresses Cell Growth in Head and Neck Squamous Cell Carcinoma Through Inhibition of PFKFB3-Mediated Warburg Effect</p>

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