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/EBPδ, NF-IL6β) 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.

CCAAT/enhancer binding protein delta (C/EBPδ, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage

“…This study, together with two recent reports (25,31), underscores a multifaceted impact of C/EBPδ on the DNA damage response. By promoting cyclin D1 degradation (25), C/EBPδ may augment growth arrest to allow DNA repair to proceed.…”

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

“…Moreover, STAT3 pathway inhibition has been shown to result in growth arrest, apoptosis, and chemosensitivity in several human malignancy models (50). We previously demonstrated that CEBPD inhibition increased UCUB sensitivity to CDDP (19). In this study, we demonstrated that CEBPD attenuation in UCUB and CDDPresistant UCUB cells sensitized them to CDDP and CDDPinduced paclitaxel resistance (Fig.…”

“…In addition to acting as a tumor suppressor, several recent reports have suggested that CEBPD plays an oncogenic role under certain conditions (17,18). Furthermore, CEBPD attenuation can sensitize CDDPinduced cell death in CDDP-resistant UCUB cells (19). However, the details remain largely unclear, and the improvement in CEBPD activation following CDDP and paclitaxel cross-resistance remains uninvestigated.…”

HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

“…CEBPD participates in the induction of genomic instability inducers, including aurora kinase C, superoxide dismutase 1 (SOD1), and COX-2 (28,44). Genomic instability has been suggestively linked to anticancer drug resistance and cancer reoccurrence (44).…”