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Journal articles
Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress
Anja Wilmes
1
Alice Limonciel
1
Lydia Aschauer
1
Konrad Moenks
Chris Bielow
Martin O. Leonard
Jeremy Hamon
2, 3
Donatella Carpi
Silke Ruzek
Andreas Handler
Olga Schmal
Karin Herrgen
Patricia Bellwon
Christof Burek
Germaine L. Truisi
Philip Hewitt
Emma Di Consiglio
Emanuela Testai
Bas J. Blaauboer
Claude Guillou
Christian G. Huber
Arno Lukas
Walter Pfaller
Stefan O. Mueller
Frédéric Y. Bois
2, 3
Wolfang Dekant
Paul Jennings
1
1
Division of Physiology, Department of Physiology and Medical Physics (Austria)
- IMU - Innsbruck Medical University [Austria] (Innrain 52, Christoph-Probst-Platz, 6020 Innsbruck - Austria)
2
INERIS - Institut National de l'Environnement Industriel et des Risques (Verneuil-en-Halatte ; Nancy ; Aix en Provence - France)
3
UTC - Université de Technologie de Compiègne (Université de Technologie de Compiègne - Centre de Recherche de Royallieu - rue du Docteur Schweitzer- CS 60319 - 60203 COMPIEGNE Cedex - France)
Abstract : High content omic techniques in combination with stable human in vitro cell culture systems have the potential to improve on current pre-clinical safety regimes by providing detailed mechanistic information of altered cellular processes. Here we investigated the added benefit of integrating transcriptomics, proteomics and metabolomics together with pharmacokinetics for drug testing regimes. Cultured human renal epithelial cells (RPTEC/TERT1) were exposed to the nephrotoxin Cyclosporine A (CsA) at therapeutic and supratherapeutic concentrations for 14 days. CsA was quantified in supernatants and cellular lysates by LC-MS/MS for kinetic modeling. There was a rapid cellular uptake and accumulation of CsA, with a non-linear relationship between intracellular and applied concentrations. CsA at 15 µM induced mitochondrial disturbances and activation of the Nrf2-oxidative-damage and the unfolded protein-response pathways. All three omic streams provided complementary information, especially pertaining to Nrf2 and ATF4 activation. No stress induction was detected with 5 µM CsA; however, both concentrations resulted in a maximal secretion of cyclophilin B. The study demonstrates for the first time that CsA-induced stress is not directly linked to its primary pharmacology. In addition we demonstrate the power of integrated omics for the elucidation of signaling cascades brought about by compound induced cell stress.
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Journal articles
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https://hal-ineris.archives-ouvertes.fr/ineris-00963456
Contributor : Gestionnaire Civs <>
Submitted on : Friday, March 21, 2014 - 2:32:02 PM
Last modification on : Friday, April 16, 2021 - 1:46:05 PM
Contributor : Gestionnaire Civs <>
Submitted on : Friday, March 21, 2014 - 2:32:02 PM
Last modification on : Friday, April 16, 2021 - 1:46:05 PM
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- HAL Id : ineris-00963456, version 1
- DOI : 10.1016/j.jprot.2012.11.022
- PUBMED : 23238060
- INERIS : EN-2013-080
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Anja Wilmes, Alice Limonciel, Lydia Aschauer, Konrad Moenks, Chris Bielow, et al.. Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress. Journal of Proteomics, Elsevier, 2013, 79, pp.180-194. ⟨10.1016/j.jprot.2012.11.022⟩. ⟨ineris-00963456⟩
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