Human Placental Fructose-6-phosphate,2-kinase/Fructose-2,6-bisphosphatase: Its Isozymic Form, Expression and Characterization

Sakakibara, Ryuzo; Uemura, Mika; Hirata, Takafumi; Okamura, Noriko; Kato, Mie

doi:10.1271/bbb.61.1949

Cited by 21 publications

(12 citation statements)

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“…It was nearly a century ago when Warburg described that cancer cells show characteristic metabolic alterations which make them highly dependent on glycolysis for survival and spreading . PFKFB3 gene is overexpressed in tumours and codes for the PFKFB3 isoenzyme of PFK‐2/FBPase‐2, which has the highest kinase/bisphosphatase ratio and maintains a high Fru‐2,6‐P 2 concentration in tumour cells . The inhibition of PFKFB3 causes a glycolytic blockage that results in impaired vessel sprouting , cell cycle arrest and cell death, and reduction of anchorage‐independent growth of tumour cell colonies and animal tumour burden .…”

Section: Discussionmentioning

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 . 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 .…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

et al. 2016

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“…PFKFB4 is a bifunctional enzyme comprising kinase as well as phosphatase activity, with the latter being slightly stronger (Sakakibara et al, 1997). It regulates the steady-state concentration of fructose 2,6-bisphosphate which is an activator of PFK-1 and therefore of glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces a HIF-1α dependent signaling cascade to make a complex metabolic switch in SGBS-adipocytes

Leiherer

Geiger

Muendlein

2014

Molecular and Cellular Endocrinology

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“…The conversion of fructose 6-phosphate to fructose 1,6-bisphosphate by 6-phosphofructokinase-1 (PFK-1) is a critical step for a high glycolytic rate. The PFKFB3 isoenzyme has the highest kinase/ bisphosphatase activity ratio, favoring net synthesis of Fru-2,6-P 2 [29]. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) [EC:2.7.1.105/EC:3.1.3.46] catalyzes both the synthesis and degradation of Fru-2,6-P 2 .…”

Section: Introductionmentioning

confidence: 99%

TGF‐β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

et al. 2017

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In human cancers, transforming growth factor-β1 (TGF-β1) plays a dual role by acting as both a tumor suppressor and a promoter of tumor metastasis. Although TGF-β1 contributes to the metabolic reprogramming of cancer cells and tumor-associated stromal cells, little is known of the molecular mechanisms connecting this cytokine with enhanced glycolysis. PFKFB3 is a homodymeric bifunctional enzyme, belonging to the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases, that controls the conversion of fructose-6-phosphate (Fru-6-P) to fructose-2,6-bisphosphate (Fru-2,6-P ). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating phosphofructokinase-1, a rate-limiting enzyme in glycolysis. The PFKFB3 gene is involved in cell proliferation via its role in carbohydrate metabolism. Here, we studied the mechanisms connecting TGF-β1, glucose metabolism, and PFKFB3 in glioblastoma cell lines. We demonstrate that TGF-β1 upregulates PFKFB3 mRNA and protein expression resulting in an increase in fructose 2,6-bisphosphate concentration, glucose uptake, glycolytic flux and lactate production. Moreover, these increases in PFKFB3 mRNA and protein expression and Fru-2,6-P concentration were reduced when the Smad3, p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were inhibited. We demonstrate that inhibition of PFKFB3 activity with 3PO or siRNA-mediated knockdown of PFKFB3 significantly eliminated the capacity of the T98G cells to form colonies by TGF-β1, one of the hallmarks of transformation. Taken together, these results show that TGF-β1 induces PFKFB3 expression through activation of the p38 MAPK and PI3K/Akt signaling pathways that complement and converge with early activation of Smad signaling. This suggests that PFKFB3 induction by TGF-β1 can be one of the main mechanisms mediating the reprogramming of glioma cells.

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Human Placental Fructose-6-phosphate,2-kinase/Fructose-2,6-bisphosphatase: Its Isozymic Form, Expression and Characterization

Cited by 21 publications

References 0 publications

Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition

Hypoxia induces a HIF-1α dependent signaling cascade to make a complex metabolic switch in SGBS-adipocytes

TGF‐β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

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