Transcriptional up-regulation of SOD1 by CEBPD: a potential target for cisplatin resistant human urothelial carcinoma cells.
Bladder cancer is the fourth most common type of cancer in men (ninth in women) in the United States. Cisplatin is an effective agent against the most common subtype, urothelial carcinoma. However, the development of chemotherapy resistance is a severe clinical problem for the successful treatment of this and other cancers. A better understanding of the cellular and molecular events in response to cisplatin treatment and the development of resistance are critical to improve the therapeutic options for patients. Here, we report that expression of the CCAAT/enhancer binding protein delta (CEBPD, C/EBPdelta, NF-IL6beta) is induced by cisplatin in the human bladder urothelial carcinoma NTUB1 cell line and is specifically elevated in a cisplatin resistant subline. Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation. Several reports have implicated CEBPD as a tumor suppressor gene. This study reveals a novel role for CEBPD in conferring drug resistance, suggesting that it can also be pro-oncogenic. Furthermore, our data suggest that SOD inhibitors, which are already used as anti-angiogenic agents, may be suitable for combinatorial chemotherapy to prevent or treat cisplatin resistance in bladder and possibly other cancers.
Hour
Tzyh-Chyuan
TC
Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
Lai
Yan-Liang
YL
Kuan
Ching-I
CI
Chou
Chen-Kung
CK
Wang
Ju-Ming
JM
Tu
Huang-Yao
HY
Hu
Huei-Ting
HT
Lin
Chang-Shen
CS
Wu
Wen-Jeng
WJ
Pu
Yeong-Shiau
YS
Sterneck
Esta
E
Huang
A-Mei
AM
D017209:Apoptosis / Q000235:genetics; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014571:Urologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
C497252:CEBPD protein, human; C000606290:SOD1 protein, human; D051743:CCAAT-Enhancer-Binding Protein-delta; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002945:Cisplatin
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