Format

Send to

Choose Destination
Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27. doi: 10.1016/j.tiv.2014.10.006. Epub 2014 Oct 23.

Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics.

Author information

1
Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck 6020, Austria. Electronic address: Anja.Wilmes@i-med.ac.at.
2
Institute of Computer Science, Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin 14195, Germany.
3
Department of Molecular Biology, Division of Chemistry and Bioanalytics, University of Salzburg, Salzburg 5020, Austria.
4
Department of Toxicology, University of Würzburg, Würzburg 97078, Germany.
5
Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck 6020, Austria.
6
European Commission, Joint Research Centre (JRC), Institute for Health and Consumer Protection, Chemical Assessment and Testing Unit, Via Enrico Fermi 2749, I-21027 Ispra, Italy.
7
Merck KGaA, Merck Serono, Nonclinical Safety, Darmstadt 64293, Germany.
8
Centre for Radiation, Chemical and Environmental Hazard, Public Health England, Chilton, Didcot OX11 0RQ, UK.
9
Université de Technologie de Compiègne, Compiègne Cedex 60205, France.

Abstract

Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of solid tumours. The major dose-limiting factor is nephrotoxicity, in particular in the proximal tubule. Here, we use an integrated omics approach, including transcriptomics, proteomics and metabolomics coupled to biokinetics to identify cell stress response pathways induced by cisplatin. The human renal proximal tubular cell line RPTEC/TERT1 was treated with sub-cytotoxic concentrations of cisplatin (0.5 and 2 μM) in a daily repeat dose treating regime for up to 14 days. Biokinetic analysis showed that cisplatin was taken up from the basolateral compartment, transported to the apical compartment, and accumulated in cells over time. This is in line with basolateral uptake of cisplatin via organic cation transporter 2 and bioactivation via gamma-glutamyl transpeptidase located on the apical side of proximal tubular cells. Cisplatin affected several pathways including, p53 signalling, Nrf2 mediated oxidative stress response, mitochondrial processes, mTOR and AMPK signalling. In addition, we identified novel pathways changed by cisplatin, including eIF2 signalling, actin nucleation via the ARP/WASP complex and regulation of cell polarization. In conclusion, using an integrated omic approach together with biokinetics we have identified both novel and established mechanisms of cisplatin toxicity.

KEYWORDS:

Autophagy; Biokinetics; Cisplatin; Omics; Proximal tubule; Stress response pathways

PMID:
25450742
DOI:
10.1016/j.tiv.2014.10.006
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center