β-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner : = [Beta]-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner

Abstract: Inositol pyrophosphates (PP-InsPs) are energetic signaling molecules with important functions in mammals. As their biosynthesis depends on ATP concentration, PP-InsPs are tightly connected to cellular energy homeostasis. Consequently, an increasing number of studies involve PP-InsPs in metabolic disorders, such as type 2 diabetes, aspects of tumorigenesis, and hyperphosphatemia. Research conducted in yeast suggests that the PP-InsP pathway is activated in response to reactive oxygen species (ROS). However, the precise modulation of PP-InsPs during cellular ROS signaling is unknown. Here, we report how mammalian PP-InsP levels are changing during exposure to exogenous (H2O2) and endogenous ROS. Using capillary electrophoresis electrospray ionization mass spectrometry (CE-ESI-MS), we found that PP-InsP levels decrease upon exposure to oxidative stressors in HCT116 cells. Application of quinone drugs, particularly β-lapachone (β-lap), under normoxic and hypoxic conditions enabled us to produce ROS in cellulo and to show that β-lap treatment caused PP-InsP changes that are oxygen-dependent. Experiments in MDA-MB-231 breast cancer cells deficient of NAD(P)H:quinone oxidoreductase-1 (NQO1) demonstrated that β-lap requires NQO1 bioactivation to regulate the cellular metabolism of PP-InsPs. Critically, significant reductions in cellular ATP concentrations were not directly mirrored in reduced PP-InsP levels as shown in NQO1-deficient MDA-MB-231 cells treated with β-lap. The data presented here unveil unique aspects of β-lap pharmacology and its impact on PP-InsP levels. The identification of different quinone drugs as modulators of PP-InsP synthesis will allow the overall impact on cellular function of such drugs to be better appreciated

Angaben zum Objekt

• Weitere Titel: [Beta]-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner
• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Proceedings of the National Academy of Sciences of the United States of America. - 120, 34 (2023) , e2306868120, ISSN: 1091-6490

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2023
• Urheber: Eisenbeis, Verena B. ; Qiu, Danye ; Gorka, Oliver ; Strotmann, Lisa ; Liu, Guizhen ; Prucker, Isabel ; Su, Xue Bessie ; Wilson, Miranda S. C. ; Ritter, Kevin ; Lönarz, Christoph ; Groß, Olaf ; Saiardi, Adolfo ; Jessen, Henning Jacob

Weitere Informationen

• DOI: 10.1073/pnas.2306868120
• URN: urn:nbn:de:bsz:25-freidok-2389113
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 01.03.2025, 13:12 MEZ