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

Abstract

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.

• Authors: Jonas Aakre Wik, Peter Lundbäck, Lars la Cour Poulsen, Guttorm Haraldsen, Bjørn Steen Skålhegg, Johanna Hol
• Journal: PloS one (PLoS One) Vol. 15 Issue 3 Pg. e0229395 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 32130250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one
• Interleukin-1beta
• NF-kappa B
• Pyridines
• Tumor Necrosis Factor-alpha
• PFKFB3 protein, human
• Phosphofructokinase-2
• I-kappa B Kinase
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases

Topics

• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• I-kappa B Kinase (metabolism)
• Inflammation (metabolism, pathology)
• Interleukin-1beta (pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Phosphofructokinase-2 (metabolism)
• Phosphorylation (drug effects)
• Pyridines (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)