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

Anja Wilmes, Chris Bielow, Christina Ranninger, Patricia Bellwon, Lydia Aschauer, Alice Limonciel, Hubert Chassaigne, Theresa Kristl, Stephan Aiche, Christian G Huber, Claude Guillou, Philipp Hewitt, Martin O Leonard, Wolfgang Dekant, Frederic Y Bois, Paul Jennings

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)117-27
Number of pages11
JournalToxicology in Vitro
Volume30
Issue number1 Pt A
DOIs
Publication statusPublished - 25 Dec 2015
Externally publishedYes

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Keywords

  • Cell Line
  • Cisplatin
  • Gene Expression Regulation
  • Humans
  • Kidney Tubules, Proximal
  • Metabolic Networks and Pathways
  • Metabolomics
  • Models, Biological
  • Proteomics
  • Transcriptome
  • Journal Article
  • Research Support, Non-U.S. Gov't

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