title: Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics.
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.
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck 6020, Austria. Electronic address: Anja.Wilmes@i-med.ac.at.
authors.forename: Anja
authors.initials: A
authors.lastname: Wilmes
authors.affiliation: Institute of Computer Science, Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin 14195, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Bielow
authors.affiliation: Department of Molecular Biology, Division of Chemistry and Bioanalytics, University of Salzburg, Salzburg 5020, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Ranninger
authors.affiliation: Department of Toxicology, University of Würzburg, Würzburg 97078, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bellwon
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Lydia
authors.initials: L
authors.lastname: Aschauer
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Alice
authors.initials: A
authors.lastname: Limonciel
authors.affiliation: 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.
authors.forename: Hubert
authors.initials: H
authors.lastname: Chassaigne
authors.affiliation: Department of Molecular Biology, Division of Chemistry and Bioanalytics, University of Salzburg, Salzburg 5020, Austria.
authors.forename: Theresa
authors.initials: T
authors.lastname: Kristl
authors.affiliation: Institute of Computer Science, Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin 14195, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Aiche
authors.affiliation: Department of Toxicology, University of Würzburg, Würzburg 97078, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Huber
authors.affiliation: 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.
authors.forename: Claude
authors.initials: C
authors.lastname: Guillou
authors.affiliation: Merck KGaA, Merck Serono, Nonclinical Safety, Darmstadt 64293, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Hewitt
authors.affiliation: Centre for Radiation, Chemical and Environmental Hazard, Public Health England, Chilton, Didcot OX11 0RQ, UK.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leonard
authors.affiliation: Department of Toxicology, University of Würzburg, Würzburg 97078, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dekant
authors.affiliation: Université de Technologie de Compiègne, Compiègne Cedex 60205, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bois
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Jennings
mesh_terms: D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D055432:Metabolomics; D008954:Models, Biological; D040901:Proteomics; D059467:Transcriptome
chemical_list: D002945:Cisplatin
keywords: Autophagy; Biokinetics; Cisplatin; Omics; Proximal tubule; Stress response pathways