Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors

PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplas...

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Autores principales:	Reinier Alvarez, Debjani Mandal, Prashant Chittiboina
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	PFKFB3 PFK-2 tumorigenic reprogramming metabolic reprogramming hypoxia glycolysis Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1b1980bd9c8a4433aaa7491ce614c0ba
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spelling	oai:doaj.org-article:1b1980bd9c8a4433aaa7491ce614c0ba2021-11-25T17:08:50ZCanonical and Non-Canonical Roles of PFKFB3 in Brain Tumors10.3390/cells101129132073-4409https://doaj.org/article/1b1980bd9c8a4433aaa7491ce614c0ba2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2913https://doaj.org/toc/2073-4409PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors.Reinier AlvarezDebjani MandalPrashant ChittiboinaMDPI AGarticlePFKFB3PFK-2tumorigenic reprogrammingmetabolic reprogramminghypoxiaglycolysisBiology (General)QH301-705.5ENCells, Vol 10, Iss 2913, p 2913 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PFKFB3 PFK-2 tumorigenic reprogramming metabolic reprogramming hypoxia glycolysis Biology (General) QH301-705.5
spellingShingle	PFKFB3 PFK-2 tumorigenic reprogramming metabolic reprogramming hypoxia glycolysis Biology (General) QH301-705.5 Reinier Alvarez Debjani Mandal Prashant Chittiboina Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
description	PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors.
format	article
author	Reinier Alvarez Debjani Mandal Prashant Chittiboina
author_facet	Reinier Alvarez Debjani Mandal Prashant Chittiboina
author_sort	Reinier Alvarez
title	Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
title_short	Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
title_full	Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
title_fullStr	Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
title_full_unstemmed	Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
title_sort	canonical and non-canonical roles of pfkfb3 in brain tumors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1b1980bd9c8a4433aaa7491ce614c0ba
work_keys_str_mv	AT reinieralvarez canonicalandnoncanonicalrolesofpfkfb3inbraintumors AT debjanimandal canonicalandnoncanonicalrolesofpfkfb3inbraintumors AT prashantchittiboina canonicalandnoncanonicalrolesofpfkfb3inbraintumors
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Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors

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