کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5861295 1133757 2015 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics
ترجمه فارسی عنوان
مکانیسم سمیت پروتئینهای سیس پلاتین با استفاده از یکپارچه سازی ترانسکتنیک، پروتئومیک، متابولومویک و بیو کینتیک
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
چکیده انگلیسی


- Integrated omics provided a deep mechanistic insight of cisplatin induced proximal tubule toxicity.
- Altered stress response pathways include p53, Nrf2, mitochondrial dysfunction, AMPK, mTOR, eIF2 and actin nucleation via ARP.
- Biokinetic modelling revealed a basolateral uptake, apical secretion and cellular accumulation of cisplatin.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology in Vitro - Volume 30, Issue 1, Part A, 25 December 2015, Pages 117-127
نویسندگان
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