| Summary: | 碩士 === 高雄醫學大學 === 生物化學研究所 === 97 === 英文摘要
Cisplatin (cis-diaminedichloroplatinum;CDDP), a platinum- based anticancer drug, is one of the most effective chemo- therapeutic agents. Its configuration includes two amines, two chlorines, and the center of platinum. The cytotoxic effect of cisplatin is mainly mediated by DNA damage, primarily forming intrastrand crosslinking DNA adducts and ROS production. However, its clinical efficacy is largely limited to its toxic effects on normal cells and the development of drug resistance within tumor cells. Therefore, understanding the molecular and cellular events upon cisplatin treatment will improve the development of therapeutic options for the patients. CCAAT/enhancer-binding protein delta (CEBPD) belongs to C/EBP transcription factor family. We previously found CEBPD mRNA and protein were induced by cisplatin in human urothelial carcinoma cell line NTUB1. In order to explore the biological roles of CEBPD in cisplatin response and resistance, various CEBPD- expressing stable clones in NTUB1 were established: N-V (empty vector pcDNA3); N-D#1 (WT, CEBPD full length); N-△DBD (Mutant, C-terminal basic leucine zipper domain of CEBPD 197-269 amino acids was deleted); N-R198A (Mutant, CEBPD amino acid198 Arginine was replaced by Alanine) and N-hd-pSi (CEBPD siRNA knocking down). The results showed that C-terminal DNA binding domain activity of CEBPD is essential for the cisplatin response and resistance. Furthermore, SOD1 was identified as a direct target of CEBPD and contributed to CEBPD-mediated cisplatin resistance in NTUB1 cells. Thus, CEBPD might be a potential target for clinical treatment of cisplatin resistant bladder cancers. The underlying molecular mechanism of CEBPD-mediated SOD1 expression in cisplatin response/resistance needs to be further explored.
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