PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3)

Novellasdemunt, Laura; Navarro-Sabaté, Àurea; Manzano, Ànna; Rodríguez-García, Ana; Bartrons, Ramón

doi:10.4267/2042/51425

Cited by 3 publications

(3 citation statements)

References 31 publications

(64 reference statements)

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“…PFKFB3 is constitutively overexpressed in different cancer cell lines and in several human leukemias and solid tumors ( 140 , 141 ), including ovarian and thyroid carcinomas ( 142 ), colon adenocarcinoma, breast cancer, gastric tumors and pancreatic cancer ( 73 , 87 , 111 , 113 , 143 ), and has been associated with lymph node metastasis and the TNM stage ( 143 ). PFKFB3 can also represent a biomarker and an anti-neoplastic target in gastric cancer ( 144 ).…”

Section: Reprogramming the Glycolytic Phenotype Of Cancer Cellsmentioning

confidence: 99%

Fructose 2,6-Bisphosphate in Cancer Cell Metabolism

et al. 2018

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For a long time, pioneers in the field of cancer cell metabolism, such as Otto Warburg, have focused on the idea that tumor cells maintain high glycolytic rates even with adequate oxygen supply, in what is known as aerobic glycolysis or the Warburg effect. Recent studies have reported a more complex situation, where the tumor ecosystem plays a more critical role in cancer progression. Cancer cells display extraordinary plasticity in adapting to changes in their tumor microenvironment, developing strategies to survive and proliferate. The proliferation of cancer cells needs a high rate of energy and metabolic substrates for biosynthesis of biomolecules. These requirements are met by the metabolic reprogramming of cancer cells and others present in the tumor microenvironment, which is essential for tumor survival and spread. Metabolic reprogramming involves a complex interplay between oncogenes, tumor suppressors, growth factors and local factors in the tumor microenvironment. These factors can induce overexpression and increased activity of glycolytic isoenzymes and proteins in stromal and cancer cells which are different from those expressed in normal cells. The fructose-6-phosphate/fructose-1,6-bisphosphate cycle, catalyzed by 6-phosphofructo-1-kinase/fructose 1,6-bisphosphatase (PFK1/FBPase1) isoenzymes, plays a key role in controlling glycolytic rates. PFK1/FBpase1 activities are allosterically regulated by fructose-2,6-bisphosphate, the product of the enzymatic activity of the dual kinase/phosphatase family of enzymes: 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB1-4) and TP53-induced glycolysis and apoptosis regulator (TIGAR), which show increased expression in a significant number of tumor types. In this review, the function of these isoenzymes in the regulation of metabolism, as well as the regulatory factors modulating their expression and activity in the tumor ecosystem are discussed. Targeting these isoenzymes, either directly or by inhibiting their activating factors, could be a promising approach for treating cancers.

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Section: Reprogramming the Glycolytic Phenotype Of Cancer Cellsmentioning

confidence: 99%

Fructose 2,6-Bisphosphate in Cancer Cell Metabolism

et al. 2018

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“…Importantly, tissue‐specific isoenzymes are not totally exclusive and cells and tissues can express more than one to respond to different physiological conditions or stimuli . The PFKFB3 isoenzyme has a high kinase/bisphosphatase activity ratio, which makes it a net producer of Fru‐2,6‐P 2 , and it is overexpressed in proliferative cells and tumours . PFKFB3 suppression decreases Fru‐2,6‐P 2 and lactate production, apoptosis, inhibition of anchorage‐independent colony formation and impaired vessel sprouting and tumour growth .…”

mentioning

confidence: 99%

“…Importantly, tissue-specific isoenzymes are not totally exclusive and cells and tissues can express more than one to respond to different physiological conditions or stimuli [6,9]. The PFKFB3 isoenzyme has a high kinase/bisphosphatase activity ratio, which makes it a net producer of Fru-2,6-P 2 , and it is overexpressed in proliferative cells [10][11][12] and tumours [13][14][15][16][17][18]. Abbreviations 2,3-BPG, 2,3-bisphosphoglycerate; BHA, butylated hydroxyanisole; DCFDA, 2 0 ,7 0 -dichlorofluorescein diacetate; DMEM, Dulbecco's modified eagle's medium; FACS, fluorescence-activated cell sorting; Fru-2,6-P 2 , fructose 2,6-bisphosphate; HBSS, Hank's balanced salt solution; PFK-1, phosphofructokinase-1; PFK-2/FBPase-2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PI, propidium iodide; ROS, reactive oxygen species; siRNA, small interfering RNA; TIGAR, TP53-induced glycolysis and apoptosis regulator; PPP, pentose phosphate pathway.…”

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confidence: 99%

Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

et al. 2016

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Neoplastic cells metabolize higher amounts of glucose relative to normal cells in order to cover increased energetic and anabolic needs. Inhibition of the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) diminishes cancer cell proliferation and tumour growth in animals. In this work, we investigate the crosstalk between PFKFB3 and TIGAR (TP53-Induced Glycolysis and Apoptosis Regulator), a protein known to protect cells from oxidative stress. Our results show consistent TIGAR induction in HeLa cells in response to PFKFB3 knockdown. Upon PFKFB3 silencing, cells undergo oxidative stress and trigger Akt phosphorylation. This leads to induction of a TIGAR-mediated prosurvival pathway that reduces both oxidative stress and cell death. As TIGAR is known to have a role in DNA repair, it could serve as a potential target for the development of effective antineoplastic therapies.

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