Distinct mechanisms contribute to acquired cisplatin resistance of urothelial carcinoma cells
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Annika Höhn1, Katharina Krüger1, Margaretha A. Skowron2, Stefanie Bormann1, Lena Schumacher1, Wolfgang A. Schulz2, Michèle J. Hoffmann2, Günter Niegisch2, Gerhard Fritz1
1Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
2Department of Urology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
Gerhard Fritz, email: firstname.lastname@example.org
Keywords: cisplatin, urothelial carcinoma, DNA damage response, DNA repair, cisplatin resistance
Received: October 07, 2015 Accepted: April 22, 2016 Published: May 12, 2016
Cisplatin (CisPt) is frequently used in the therapy of urothelial carcinoma (UC). Its therapeutic efficacy is limited by inherent or acquired drug resistance. Here, we comparatively investigated the CisPt-induced response of two different parental urothelial carcinoma cell lines (RT-112, J-82) with that of respective drug resistant variants (RT-112R, J-82R) obtained upon month-long CisPt selection. Parental RT-112 cells were ~2.5 fold more resistant to CisPt than J-82 cells and showed a different expression pattern of CisPt-related resistance factors. CisPt resistant RT-112R and J-82R variants revealed a 2–3-fold increased CisPt resistance as compared to their corresponding parental counterparts. Acquired CisPt resistance was accompanied by morphological alterations resembling epithelial mesenchymal transition (EMT). RT-112R cells revealed lower apoptotic frequency and more pronounced G2/M arrest following CisPt exposure than RT-112 cells, whereas no differences in death induction were observed between J-82 and J-82R cells. CisPt resistant J-82R cells however were characterized by a reduced formation of CisPt-induced DNA damage and related DNA damage response (DDR) as compared to J-82 cells. Such difference was not observed between RT-112R and RT-112 cells. J-82R cells showed an enhanced sensitivity to pharmacological inhibition of checkpoint kinase 1 (Chk1) and, moreover, could be re-sensitized to CisPt upon Chk1 inhibition. Based on the data we suggest that mechanisms of acquired CisPt resistance of individual UC cells are substantially different, with apoptosis- and DDR-related mechanisms being of particular relevance. Moreover, the findings indicate that targeting of Chk1 might be useful to overcome acquired CisPt resistance of certain subtypes of UC.
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