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3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3

PloS one, 2020, Vol.15 (3), p.e0229395-e0229395 [Peer Reviewed Journal]

2020 Wik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;info:eu-repo/semantics/openAccess ;2020 Wik et al 2020 Wik et al ;ISSN: 1932-6203 ;EISSN: 1932-6203 ;DOI: 10.1371/journal.pone.0229395 ;PMID: 32130250

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Title:
3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3
Author: Wik, Jonas Aakre ; Lundbäck, Peter ; la Cour Poulsen, Lars ; Haraldsen, Guttorm ; Skålhegg, Bjørn Steen ; Hol, Johanna
Ushio-Fukai, Masuko
Subjects: 6-Phosphofructokinase ; Angiogenesis ; Biology and Life Sciences ; Cell activation ; Cell adhesion & migration ; Cell cycle ; Cell migration ; Cell proliferation ; Clinical medicine ; Cloning ; Cyclin-dependent kinases ; Cytokines ; E-selectin ; Endothelial cells ; Enzymes ; Fructose ; Glycolysis ; Hypoxia ; IL-1β ; Immunoglobulins ; Inflammation ; Inhibition ; Kinases ; Medicine ; Medicine and Health Sciences ; Membranes ; NF-κB protein ; Pathology ; Phosphofructokinase ; Phosphorylation ; Proteins ; R&D ; Research & development ; Research and Analysis Methods ; Signaling ; Tumor necrosis factor ; Tumor necrosis factor-TNF ; Vascular cell adhesion molecule 1
Is Part Of: PloS one, 2020, Vol.15 (3), p.e0229395-e0229395
Description: Inhibition of the key glycolytic activator 6-phosphofructokinase 2/fructose-2,6-bisphosphatase-3 (PFKFB3) by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) strongly attenuates pathological angiogenesis in cancer and inflammation. In addition to modulating endothelial proliferation and migration, 3PO also dampens proinflammatory activation of endothelial cells and experimental inflammation in vivo, suggesting a potential for 3PO in the treatment of chronic inflammation. The aim of our study was to explore if the anti-inflammatory action of 3PO in human endothelial cells was mediated by inhibition of PFKFB3 and glycolysis and assess if other means of PFKFB3 inhibition reduced inflammatory activation in a similar manner. We found that 3PO caused a rapid and transient reduction in IL-1β- and TNF-induced phosphorylation of both IKKα/β and JNK, thus inhibiting signaling through the NFκB and the stress-activated kinase pathways. However, in contrast to 3PO-treatment, neither shRNA-mediated silencing of PFKFB3 nor treatment with the alternative PFKFB3 inhibitor 7,8-dihydroxy-3-(4-hydroxy-phenyl)-chromen-4-one (YN1) prevented cytokine-induced NFκB signaling and upregulation of the adhesion molecules VCAM-1 and E-selectin, implying off target effects of 3PO. Collectively, our results suggest that the anti-inflammatory action of 3PO in human endothelial cells is not limited to inhibition of PFKFB3 and cellular glycolysis.
Publisher: United States: Public Library of Science
Language: English;Norwegian
Identifier: ISSN: 1932-6203
EISSN: 1932-6203
DOI: 10.1371/journal.pone.0229395
PMID: 32130250
Source: Geneva Foundation Free Medical Journals at publisher websites
AUTh Library subscriptions: ProQuest Central
PLoS
NORA Norwegian Open Research Archives
PubMed Central
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3PO inhibits inflammatory NFκB and stress-activated kinase signaling in primary human endothelial cells independently of its target PFKFB3

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