Title: Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress.
Authors: WILMES AnjaLIMONCIEL AliceASCHAUER LydiaMOENKS KonradBIELOW ChrisLEONARD MatrinHAMON JeremyCARPI DonatellaRUZEK SilkeHANDLER AndreasSCHMAL OlgaHERRGEN KarinBELLWON PatriciaBUREK ChristofTRUISI GermaineHEWITT PhilipDI CONSIGLIO EmmaTESTAI EmanuelaBLAAUBOER Bas J.GUILLOU ClaudeHUBER ChristianLUKAS ArnoPFALLER WalterMUELLER StefanBOIS FredericDEKANT WolfgangJENNINGS Paul
Citation: JOURNAL OF PROTEOMICS vol. 79 p. 180-194
Publisher: ELSEVIER SCIENCE BV
Publication Year: 2013
JRC N°: JRC77136
ISSN: 1874-3919
URI: http://www.sciencedirect.com/science/article/pii/S1874391912007774
http://publications.jrc.ec.europa.eu/repository/handle/JRC77136
DOI: 10.1016/j.jprot.2012.11.022
Type: Articles in periodicals and books
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 characterized nephrotoxin Cyclosporine A (CsA) at therapeutic and supra therapeutic 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.
JRC Directorate:Institute for Health and Consumer Protection Historical Collection

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