Academic Journal
Tankyrase1/2 inhibitor XAV-939 reverts EMT and suggests that PARylation partially regulates aerobic activities in human hepatocytes and HepG2 cells
| العنوان: | Tankyrase1/2 inhibitor XAV-939 reverts EMT and suggests that PARylation partially regulates aerobic activities in human hepatocytes and HepG2 cells |
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| المؤلفون: | De Vos, Kristof, Mavrogiannis, Adamantios, Clarinda Wolters, Justina, Schlenner, Susan, Wierda, Keimpe, Cortés Calabuig, Álvaro, Chinnaraj, Reena, Dermesrobian, Vera, Armoudjian, Yeghig, Jacquemyn, Maarten, Corthout, Nikky, Daelemans, Dirk, Annaert, Pieter |
| المصدر: | De Vos , K , Mavrogiannis , A , Clarinda Wolters , J , Schlenner , S , Wierda , K , Cortés Calabuig , Á , Chinnaraj , R , Dermesrobian , V , Armoudjian , Y , Jacquemyn , M , Corthout , N , Daelemans , D & Annaert , P 2024 , ' Tankyrase1/2 inhibitor XAV-939 reverts EMT and suggests that PARylation partially regulates aerobic activities in human hepatocytes and HepG2 cells ' , Biochemical Pharmacology , vol. 227 , 116445 . https://doi.org/10.1016/j.bcp.2024.116445 |
| سنة النشر: | 2024 |
| المجموعة: | University of Groningen research database |
| مصطلحات موضوعية: | CYP450 biotransformation, Mitochondrial function, Poly-ADP-ribosylation, Sandwich-cultured human hepatocytes, Tankyrase1/2, XAV-939 |
| الوصف: | The maintenance of a highly functional metabolic epithelium in vitro is challenging. Metabolic impairments in primary human hepatocytes (PHHs) over time is primarily due to epithelial-to-mesenchymal transitioning (EMT). The immature hepatoma cell line HepG2 was used as an in vitro model to explore strategies for enhancing the hepatic phenotype. The phenotypic characterization includes measuring the urea cycle, lipid storage, tricarboxylic acid-related metabolites, reactive oxygen species, endoplasmic reticulum calcium efflux, mitochondrial membrane potentials, oxygen consumptions rate, and CYP450 biotransformation capacity. Expression studies were performed with transcriptomics, co-immunoprecipitation and proteomics. CRISPR/Cas9 was also employed to genetically engineer HepG2 cells. After confirming that PHHs develop an EMT phenotype, expression of tankyrase1/2 was found to increase over time. EMT was reverted when blocking tankyrases1/2-dependent poly-ADP-ribosylation (PARylation) activity, by biochemical and genetic perturbation. Wnt/β-catenin inhibitor XAV-939 blocks tankyrase1/2 and treatment elevated several oxygen-consuming reactions (electron-transport chain, OXHPOS, CYP450 mono-oxidase activity, phase I/II xenobiotic biotransformation, and prandial turnover), suggesting that cell metabolism was enhanced. Glutathione-dependent redox homeostasis was also significantly improved in the XAV-939 condition. Oxygen consumption rate and proteomics experiments in tankyrase1/2 double knockout HepG2 cells then uncovered PARylation as master regulator of aerobic-dependent cell respiration. Furthermore, novel tankyrase1/2-dependent PARylation targets, including mitochondrial DLST, and OGDH, were revealed. This work exposed a new mechanistic framework by linking PARylation to respiration and metabolism, thereby broadening the current understanding that underlies these vital processes. XAV-939 poses an immediate and straightforward strategy to improve aerobic activities, and metabolism, in (immature) cell cultures. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1016/j.bcp.2024.116445 |
| الاتاحة: | https://hdl.handle.net/11370/7d88a88b-d78a-48da-abae-4f56415d1072 https://research.rug.nl/en/publications/7d88a88b-d78a-48da-abae-4f56415d1072 https://doi.org/10.1016/j.bcp.2024.116445 https://pure.rug.nl/ws/files/1129091347/1-s2.0-S0006295224004283-main.pdf http://www.scopus.com/inward/record.url?scp=85199771041&partnerID=8YFLogxK |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.4657983C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.bcp.2024.116445 |
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