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Int. J. Mol. Sci. 2017, 18(8), 1680; doi:10.3390/ijms18081680

Various Mechanisms Involve the Nuclear Factor (Erythroid-Derived 2)-Like (NRF2) to Achieve Cytoprotection in Long-Term Cisplatin-Treated Urothelial Carcinoma Cell Lines

1
Department of Urology, Medical Faculty, Heinrich-Heine-University, Duesseldorf 40225, Germany
2
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf 40225, Germany
3
Department of Urology, Maastricht University Medical Centre, Maastricht 6202AZ, The Netherlands
4
Department of Obstetrics and Gynaecology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht 6229HX, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 30 June 2017 / Revised: 21 July 2017 / Accepted: 27 July 2017 / Published: 2 August 2017
(This article belongs to the Special Issue Nrf2 in Redox Signaling: A Double Edged Sword)
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Abstract

Therapeutic efficacy of cisplatin-based chemotherapy for advanced-stage urothelial carcinoma (UC) is limited by drug resistance. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway is a major regulator of cytoprotective responses. We investigated its involvement in cisplatin resistance in long-term cisplatin treated UC cell lines (LTTs). Expression of NRF2 pathway components and targets was evaluated by qRT-PCR and western blotting in LTT sublines from four different parental cells. NRF2 transcriptional activity was determined by reporter assays and total glutathione (GSH) was quantified enzymatically. Effects of siRNA-mediated NRF2 knockdown on chemosensitivity were analysed by viability assays, γH2AX immunofluorescence, and flow cytometry. Increased expression of NRF2, its positive regulator p62/SQSTM1, and elevated NRF2 activity was observed in 3/4 LTTs, which correlated with KEAP1 expression. Expression of cytoprotective enzymes and GSH concentration were upregulated in some LTTs. NRF2 knockdown resulted in downregulation of cytoprotective enzymes and resensitised 3/4 LTTs towards cisplatin as demonstrated by reduced IC50 values, increased γH2AX foci formation, and elevated number of apoptotic cells. In conclusion, while LTT lines displayed diversity in NRF2 activation, NRF2 signalling contributed to cisplatin resistance in LTT lines, albeit in diverse ways. Accordingly, inhibition of NRF2 can be used to resensitise UC cells to cisplatin, but responses in patients may likewise be variable. View Full-Text
Keywords: urothelial carcinoma (UC); cisplatin resistance; nuclear factor (erythroid-derived 2)-like 2 (NRF2); sequestosome 1 (p62/SQSTM1); Kelch-like ECH-associated protein 1 (KEAP1); cytoprotection; glutathione; nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway; hippo pathway urothelial carcinoma (UC); cisplatin resistance; nuclear factor (erythroid-derived 2)-like 2 (NRF2); sequestosome 1 (p62/SQSTM1); Kelch-like ECH-associated protein 1 (KEAP1); cytoprotection; glutathione; nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway; hippo pathway
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Skowron, M.A.; Niegisch, G.; Albrecht, P.; van Koeveringe, G.; Romano, A.; Albers, P.; Schulz, W.A.; Hoffmann, M.J. Various Mechanisms Involve the Nuclear Factor (Erythroid-Derived 2)-Like (NRF2) to Achieve Cytoprotection in Long-Term Cisplatin-Treated Urothelial Carcinoma Cell Lines. Int. J. Mol. Sci. 2017, 18, 1680.

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