Eisenbeis, Verena B;
Qiu, Danye;
Gorka, Oliver;
Strotmann, Lisa;
Liu, Guizhen;
Prucker, Isabel;
Su, Xue Bessie;
... Jessen, Henning J; + view all
(2023)
β-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner.
Proceedings of the National Academy of Sciences
, 120
(34)
, Article e2306868120. 10.1073/pnas.2306868120.
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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 (H 2 O 2 ) 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.
| Type: | Article |
|---|---|
| Title: | β-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.2306868120 |
| Publisher version: | https://doi.org/10.1073/pnas.2306868120 |
| Language: | English |
| Additional information: | Copyright © 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). |
| Keywords: | β-lapachone | ROS | inositol pyrophosphates | hypoxia | NQO1 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10175641 |
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