GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells
Britta Majchrzak-Stiller, Marie Buchholz, Ilka Peters, Daniel Waschestjuk, Johanna Strotmann, Philipp Höhn, Stephan Hahn, Chris Braumann, Waldemar Uhl, Thomas Müller, Hanns Möhler, Britta Majchrzak-Stiller, Marie Buchholz, Ilka Peters, Daniel Waschestjuk, Johanna Strotmann, Philipp Höhn, Stephan Hahn, Chris Braumann, Waldemar Uhl, Thomas Müller, Hanns Möhler
Abstract
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-κB (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-κB.
Keywords: GP-2250; NFκB; ROS; aerobic glycolysis; apoptosis; pancreatic cancer; proliferation.
Conflict of interest statement
BM‐S, MB, IP, DW, JS, PH, WU are employees of Department of General and Visceral Surgery, St. Josef‐Hospital, Germany, which received research funding from Geistlich Pharma AG to conduct the study.HM received consultancy fees from Geistlich Pharma AG. TM is employed by Geistlich Pharma AG, Wolhusen, Switzerland (Geistlich). Beyond the contribution of one author (who provided chemical expertise of the analysed agent) Geistlich had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. All other authors declare no competing interests.
© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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