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Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 23(2)
- Publication Year :
- 2015
-
Abstract
- Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy. Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity. Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel. Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201. Clin Cancer Res; 23(2); 503–13. ©2016 AACR.
- Subjects :
- inorganic chemicals
0301 basic medicine
CCAAT-Enhancer-Binding Protein-delta
STAT3 Transcription Factor
Cancer Research
Paclitaxel
Pharmacology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Gefitinib
In vivo
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
STAT3
neoplasms
Cisplatin
biology
Multidrug resistance-associated protein 2
Benzenesulfonates
Carcinoma
Cancer
Combination chemotherapy
medicine.disease
female genital diseases and pregnancy complications
Multidrug Resistance-Associated Protein 2
ErbB Receptors
Gene Expression Regulation, Neoplastic
Aminosalicylic Acids
030104 developmental biology
Oncology
chemistry
Urinary Bladder Neoplasms
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
biology.protein
Cancer research
Quinazolines
Urothelium
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 23
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....4879cb266151695ebb42bf4f3eca1d5c