期刊
ONCOTARGET
卷 7, 期 27, 页码 41320-41335出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9321
关键词
cisplatin; urothelial carcinoma; DNA damage response; DNA repair; cisplatin resistance
资金
- Strategischer Forschungsfond (SFF) of the Heinrich Heine University Dusseldorf
- Duesseldorf School of Oncology - Comprehensive Cancer Centre Dusseldorf/Deutsche Krebshilfe
- Duesseldorf School of Oncology - Medical Faculty of the Heinrich-Heine-University Dusseldorf
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-112(R), J-82(R)) obtained upon month-long CisPt selection. Parental RT-112 cells were similar to 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-112(R) and J-82(R) 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). RT112(R) 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-82(R) cells. CisPt resistant J-82(R) 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-112(R) and RT-112 cells. J-82(R) cells showed an enhanced sensitivity to pharmacological inhibition of checkpoint kinase 1 (Chk1) and, moreover, could be resensitized 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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