Transcriptional up-regulation of SOD1 by CEBPD: a potential target for cisplatin resistant human urothelial carcinoma cells.

Abstract

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.

• Authors: Tzyh-Chyuan Hour, Yan-Liang Lai, Ching-I Kuan, Chen-Kung Chou, Ju-Ming Wang, Huang-Yao Tu, Huei-Ting Hu, Chang-Shen Lin, Wen-Jeng Wu, Yeong-Shiau Pu, Esta Sterneck, A-Mei Huang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 80 Issue 3 Pg. 325-34 (Aug 01 2010) ISSN: 1873-2968 [Electronic] England
• PMID: 20385105 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright (c) 2010 Elsevier Inc. All rights reserved.

Chemical References

• CEBPD protein, human
• SOD1 protein, human
• CCAAT-Enhancer-Binding Protein-delta
• Superoxide Dismutase
• Superoxide Dismutase-1
• Cisplatin

Topics

• Apoptosis (genetics)
• CCAAT-Enhancer-Binding Protein-delta (biosynthesis, genetics, physiology)
• Cell Line, Transformed
• Cell Line, Tumor
• Cisplatin (administration & dosage)
• Drug Delivery Systems (methods)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Superoxide Dismutase (biosynthesis, genetics)
• Superoxide Dismutase-1
• Transcription, Genetic (drug effects, physiology)
• Transcriptional Activation (drug effects, physiology)
• Up-Regulation (drug effects, physiology)
• Urologic Neoplasms (drug therapy, genetics, metabolism)