An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection
- 92 Downloads
Cisplatin (CDDP) is one of the most important chemotherapeutic drugs in modern oncology. However, its use is limited by severe toxicities, which impair life quality after cancer. Here, we investigated the role of organic cation transporters (OCT) in mediating toxicities associated with chronic (twice the week for 4 weeks) low-dose (4 mg/kg body weight) CDDP treatment (resembling therapeutic protocols in patients) of wild-type (WT) mice and mice with OCT genetic deletion (OCT1/2−/−). Functional and molecular analysis showed that OCT1/2−/− mice are partially protected from CDDP-induced nephrotoxicity and peripheral neurotoxicity, whereas ototoxicity was not detectable. Surprisingly, proteomic analysis of the kidneys demonstrated that genetic deletion of OCT1/2 itself was associated with significant changes in expression of proinflammatory and profibrotic proteins which are part of an OCT-associated protein network. This signature directly regulated by OCT consisted of three classes of proteins, viz., profibrotic proteins, proinflammatory proteins, and nutrient sensing molecules. Consistent with functional protection, CDDP-induced proteome changes were more severe in WT mice than in OCT1/2−/− mice. Laser ablation-inductively coupled plasma-mass spectrometry analysis demonstrated that the presence of OCT was not associated with higher renal platinum concentrations. Taken together, these results redefine the role of OCT from passive membrane transporters to active modulators of cell signaling in the kidney.
KeywordsCisplatin Toxicities Transporters Mouse model
The authors are grateful to Dr Massimo Zucchetti from the Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, for the platinum determination in neuronal tissues. This study was supported by the Deutsche Forschungsgemeinschaft (CI 107/11-1 to MMR, AaZD, and GiC), and in part by National Institutes of Health grants (R01CA215802 to AS), and for the neurotoxicity part by a research grant from “Fondazione Banca del Monte di Lombardia” to PM.
Planned the study: UK, MS, GuC, StS, ES, HP, AS, AaZD, and GiC. Performed the experiments: AH, MMR, OBB, CK, KS, RS, CC, AlC, AnC, SaS, PM, VB, AK, DD, and GiC. Performed histological analysis: BH and VVM. Wrote the manuscript: UK, GuC, CC, HP, AS, AaZD, and GiC.
Compliance with ethical standards
Conflict of interest
The authors have declared that no conflict of interests exists.
The manuscript does not contain clinical studies or patient data.
- Jacobs C, Coleman CN, Rich L, Hirst K, Weiner MW (1984) Inhibition of cis-diamminedichloroplatinum secretion by the human kidney with probenecid. Cancer Res 44:3632–3635Google Scholar
- Qian C, Johs A, Chen H, Mann BF, Lu X, Abraham PE, Hettich RL et al (2016) Global proteome response to deletion of genes related to mercury methylation and dissimilatory metal reduction reveals changes in respiratory metabolism in geobacter sulfurreducens PCA. J Proteome Res 15:3540–3549CrossRefGoogle Scholar