title: Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Institute of Basic Medical Science, China Medical University, Taiwan R.O.C.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan R.O.C.|Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan R.O.C.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan R.O.C.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan R.O.C.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan R.O.C.
authors.forename: Yu-Yi
authors.initials: YY
authors.lastname: Chu
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan R.O.C.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan R.O.C.
authors.forename: Tzyh-Chyuan
authors.initials: TC
authors.lastname: Hour
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan R.O.C.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan R.O.C.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan R.O.C.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan R.O.C. wwwjm4721@yahoo.com.tw.|Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan R.O.C.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan R.O.C.|Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan R.O.C.
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000636:Aminosalicylic Acids / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001557:Benzenesulfonates / Q000008:administration & dosage; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D017239:Paclitaxel / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
chemical_list: C000715087:ABCC2 protein, human; D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C497252:CEBPD protein, human; D000089762:Multidrug Resistance-Associated Protein 2; C520337:NSC 74859; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051743:CCAAT-Enhancer-Binding Protein-delta; C512478:EGFR protein, human; D066246:ErbB Receptors; D017239:Paclitaxel; D002945:Cisplatin; D000077156:Gefitinib