Functional diversity of PFKFB3 splice variants in glioblastomas.

Tumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofru...

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Autores principales:	Ulli Heydasch, Renate Kessler, Jan-Peter Warnke, Klaus Eschrich, Nicole Scholz, Marina Bigl
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/37c644d889614b1ba9883c29d5338659
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spelling	oai:doaj.org-article:37c644d889614b1ba9883c29d53386592021-12-02T20:05:11ZFunctional diversity of PFKFB3 splice variants in glioblastomas.1932-620310.1371/journal.pone.0241092https://doaj.org/article/37c644d889614b1ba9883c29d53386592021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0241092https://doaj.org/toc/1932-6203Tumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2 or PFKFB). Mounting evidence suggests that cancerous tissues overexpress the PFKFB isoenzyme, PFKFB3, being causing enhanced proliferation of cancer cells. Initially, six PFKFB3 splice variants with different C-termini have been documented in humans. More recently, additional splice variants with varying N-termini were discovered the functions of which are to be uncovered. Glioblastoma is one of the deadliest forms of brain tumors. Up to now, the role of PFKFB3 splice variants in the progression and prognosis of glioblastomas is only partially understood. In this study, we first re-categorized the PFKFB3 splice variant repertoire to simplify the denomination. We investigated the impact of increased and decreased levels of PFKFB3-4 (former UBI2K4) and PFKFB3-5 (former variant 5) on the viability and proliferation rate of glioblastoma U87 and HEK-293 cells. The simultaneous knock-down of PFKFB3-4 and PFKFB3-5 led to a decrease in viability and proliferation of U87 and HEK-293 cells as well as a reduction in HEK-293 cell colony formation. Overexpression of PFKFB3-4 but not PFKFB3-5 resulted in increased cell viability and proliferation. This finding contrasts with the common notion that overexpression of PFKFB3 enhances tumor growth, but instead suggests splice variant-specific effects of PFKFB3, apparently with opposing effects on cell behaviour. Strikingly, in line with this result, we found that in human IDH-wildtype glioblastomas, the PFKFB3-4 to PFKFB3-5 ratio was significantly shifted towards PFKFB3-4 when compared to control brain samples. Our findings indicate that the expression level of distinct PFKFB3 splice variants impinges on tumorigenic properties of glioblastomas and that splice pattern may be of important diagnostic value for glioblastoma.Ulli HeydaschRenate KesslerJan-Peter WarnkeKlaus EschrichNicole ScholzMarina BiglPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0241092 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ulli Heydasch Renate Kessler Jan-Peter Warnke Klaus Eschrich Nicole Scholz Marina Bigl Functional diversity of PFKFB3 splice variants in glioblastomas.
description	Tumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2 or PFKFB). Mounting evidence suggests that cancerous tissues overexpress the PFKFB isoenzyme, PFKFB3, being causing enhanced proliferation of cancer cells. Initially, six PFKFB3 splice variants with different C-termini have been documented in humans. More recently, additional splice variants with varying N-termini were discovered the functions of which are to be uncovered. Glioblastoma is one of the deadliest forms of brain tumors. Up to now, the role of PFKFB3 splice variants in the progression and prognosis of glioblastomas is only partially understood. In this study, we first re-categorized the PFKFB3 splice variant repertoire to simplify the denomination. We investigated the impact of increased and decreased levels of PFKFB3-4 (former UBI2K4) and PFKFB3-5 (former variant 5) on the viability and proliferation rate of glioblastoma U87 and HEK-293 cells. The simultaneous knock-down of PFKFB3-4 and PFKFB3-5 led to a decrease in viability and proliferation of U87 and HEK-293 cells as well as a reduction in HEK-293 cell colony formation. Overexpression of PFKFB3-4 but not PFKFB3-5 resulted in increased cell viability and proliferation. This finding contrasts with the common notion that overexpression of PFKFB3 enhances tumor growth, but instead suggests splice variant-specific effects of PFKFB3, apparently with opposing effects on cell behaviour. Strikingly, in line with this result, we found that in human IDH-wildtype glioblastomas, the PFKFB3-4 to PFKFB3-5 ratio was significantly shifted towards PFKFB3-4 when compared to control brain samples. Our findings indicate that the expression level of distinct PFKFB3 splice variants impinges on tumorigenic properties of glioblastomas and that splice pattern may be of important diagnostic value for glioblastoma.
format	article
author	Ulli Heydasch Renate Kessler Jan-Peter Warnke Klaus Eschrich Nicole Scholz Marina Bigl
author_facet	Ulli Heydasch Renate Kessler Jan-Peter Warnke Klaus Eschrich Nicole Scholz Marina Bigl
author_sort	Ulli Heydasch
title	Functional diversity of PFKFB3 splice variants in glioblastomas.
title_short	Functional diversity of PFKFB3 splice variants in glioblastomas.
title_full	Functional diversity of PFKFB3 splice variants in glioblastomas.
title_fullStr	Functional diversity of PFKFB3 splice variants in glioblastomas.
title_full_unstemmed	Functional diversity of PFKFB3 splice variants in glioblastomas.
title_sort	functional diversity of pfkfb3 splice variants in glioblastomas.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/37c644d889614b1ba9883c29d5338659
work_keys_str_mv	AT ulliheydasch functionaldiversityofpfkfb3splicevariantsinglioblastomas AT renatekessler functionaldiversityofpfkfb3splicevariantsinglioblastomas AT janpeterwarnke functionaldiversityofpfkfb3splicevariantsinglioblastomas AT klauseschrich functionaldiversityofpfkfb3splicevariantsinglioblastomas AT nicolescholz functionaldiversityofpfkfb3splicevariantsinglioblastomas AT marinabigl functionaldiversityofpfkfb3splicevariantsinglioblastomas
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Functional diversity of PFKFB3 splice variants in glioblastomas.

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