GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-\(\kappa\)B pathway in pancreatic cancer cells

  • GP-2250, a novel anticancer agent, severely limits the energy metabolism, as demonstrated by the inhibition of hexokinase 2 and glyceraldehyde-3-phosphate dehydrogenase and a decrease of ATP. Rescue experiments with supplementary pyruvate or oxaloacetate demonstrated that a TCA cycle deficit largely contributed to cytotoxicity. Activation of the energy-deficit sensor, AMP-dependent protein kinase, was associated with increased phosphorylation of acetyl-CoA carboxylase and Raptor, pointing to a possible deficit in the synthesis of fatty acids and proteins as essential cell components. Binding of p65 to DNA was dose-dependently reduced in nuclear lysates. A transcriptional deficit of NF-\(\kappa\)B (nuclear factor kappa-light-chain-enhancer of activated B cells) was substantiated by the downregulation of cyclin D1 and of the anti-apoptotic Bcl2, in line with reduction in tumour cell proliferation and induction of apoptosis, respectively. The upregulation of p53 concomitant with an excess of ROS supported apoptosis. Thus, the anticancer activity of GP-2250 is a result of disruption of energy metabolism and inhibition of tumour promotion by NF-\(\kappa\)B.

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Author:Britta Majchrzak-StillerORCiDGND, Marie BuchholzORCiDGND, Ilka PetersORCiDGND, Daniel WaschestjukGND, Johanna Josefine StrotmannORCiDGND, Philipp HöhnORCiDGND, Stephan HahnORCiDGND, Chris BraumannORCiDGND, Waldemar UhlORCiDGND, Thomas MüllerGND, Hanns MöhlerGND
Parent Title (English):Journal of cellular and molecular medicine
Place of publication:Hoboken
Document Type:Article
Date of Publication (online):2024/02/22
Date of first Publication:2023/06/30
Publishing Institution:Ruhr-Universität Bochum, Universitätsbibliothek
Tag:Open Access Fonds
GP-2250; NF\(\kappa\)B; ROS; aerobic glycolysis; apoptosis; pancreatic cancer; proliferation
First Page:2082
Last Page:2092
Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum.
Institutes/Facilities:St. Josef-Hospital Bochum, Klinik für Allgemein- und Viszeralchirurgie
Dewey Decimal Classification:Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit
open_access (DINI-Set):open_access
Licence (English):License LogoCreative Commons - CC BY 4.0 - Attribution 4.0 International