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Integration of temporal single cell cellular stress response activity with logic-ODE modeling reveals activation of ATF4-CHOP axis as a critical predictor of drug-induced liver injury

Drug-induced liver injury (DILI) is the most prevalent adversity encountered in drug development and clinical settings leading to urgent needs to understand the underlying mechanisms. In this study, we have systematically investigated the dynamics of the activation of cellular stress response pathwa...

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Main Authors: Wijaya, Lukas Surya (Author) , Trairatphisan, Panuwat (Author) , Gabor, Attila (Author) , Niemeijer, Marije (Author) , Keet, Jason (Author) , Alcalà Morera, Ariadna (Author) , Snijders, Kirsten E. (Author) , Wink, Steven (Author) , Yang, Huan (Author) , Schildknecht, Stefan (Author) , Stevens, James L. (Author) , Bouwman, Peter (Author) , Kamp, Hennike (Author) , Hengstler, Jan (Author) , Beltman, Joost (Author) , Leist, Marcel (Author) , Le Dévédec, Sylvia (Author) , Sáez Rodríguez, Julio (Author) , van de Water, Bob (Author)
Format: Article (Journal)
Language:English
Published: 4 May 2021
In: Biochemical pharmacology
Year: 2021, Volume: 190, Pages: 1-17
ISSN:1873-2968
DOI:10.1016/j.bcp.2021.114591
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.bcp.2021.114591
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0006295221001970
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Author Notes:Lukas Surya Wijaya, Panuwat Trairatphisan, Attila Gabor, Marije Niemeijer, Jason Keet, Ariadna Alcalà Morera, Kirsten E. Snijders, Steven Wink, Huan Yang, Stefan Schildknecht, James L. Stevens, Peter Bouwman, Hennicke Kamp, Jan Hengstler, Joost Beltman, Marcel Leist, Sylvia Le Dévédec, Julio Saez-Rodriguez, Bob van de Water
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Summary:Drug-induced liver injury (DILI) is the most prevalent adversity encountered in drug development and clinical settings leading to urgent needs to understand the underlying mechanisms. In this study, we have systematically investigated the dynamics of the activation of cellular stress response pathways and cell death outcomes upon exposure of a panel of liver toxicants using live cell imaging of fluorescent reporter cell lines. We established a comprehensive temporal dynamic response profile of a large set of BAC-GFP HepG2 cell lines representing the following components of stress signaling: i) unfolded protein response (UPR) [ATF4, XBP1, BIP and CHOP]; ii) oxidative stress [NRF2, SRXN1, HMOX1]; iii) DNA damage [P53, P21, BTG2, MDM2]; and iv) NF-κB pathway [A20, ICAM1]. We quantified the single cell GFP expression as a surrogate for endogenous protein expression using live cell imaging over > 60 h upon exposure to 14 DILI compounds at multiple concentrations. Using logic-based ordinary differential equation (Logic-ODE), we modelled the dynamic profiles of the different stress responses and extracted specific descriptors potentially predicting the progressive outcomes. We identified the activation of ATF4-CHOP axis of the UPR as the key pathway showing the highest correlation with cell death upon DILI compound perturbation. Knocking down main components of the UPR provided partial protection from compound-induced cytotoxicity, indicating a complex interplay among UPR components as well as other stress pathways. Our results suggest that a systematic analysis of the temporal dynamics of ATF4-CHOP axis activation can support the identification of DILI risk for new candidate drugs.
Item Description:Gesehen am 21.10.2021
Physical Description:Online Resource
ISSN:1873-2968
DOI:10.1016/j.bcp.2021.114591

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