β-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner

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 dis...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2023-08, Vol.120 (34), p.e2306868120-e2306868120
Main Authors: Eisenbeis, Verena B, Qiu, Danye, Gorka, Oliver, Strotmann, Lisa, Liu, Guizhen, Prucker, Isabel, Su, Xue Bessie, Wilson, Miranda S C, Ritter, Kevin, Loenarz, Christoph, Groß, Olaf, Saiardi, Adolfo, Jessen, Henning J
Format: Article
Language:English
Subjects:
Adenosine Triphosphate
ATP
Biological Sciences
Biosynthesis
Capillary electrophoresis
Cell Line, Tumor
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2
Diphosphates
Drugs
Electrophoresis
Energy balance
Homeostasis
Humans
Hydrogen peroxide
Hydrogen Peroxide - metabolism
Hyperphosphatemia
Hypoxia
Inositol
Inositols
Ionization
Ions
Lapachone
Mammals
Mass spectrometry
Mass spectroscopy
Metabolic disorders
Modulators
NAD(P)H Dehydrogenase (Quinone) - genetics
NAD(P)H Dehydrogenase (Quinone) - metabolism
NADPH quinone oxidoreductase
Naphthoquinones - pharmacology
Oxygen
Pharmacology
Pyrophosphates
Quinone oxidoreductase
Quinones
Reactive oxygen species
Reactive Oxygen Species - metabolism
Tumorigenesis
Yeasts
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Summary: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 (H O ) 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2306868120