Inhibition of the EGFR/STAT3/CEBPD Axis reverses cisplatin cross-resistance with paclitaxel in the urothelial carcinoma of the urinary bladder

Wei Jan Wang, Chien Feng Li, Yu Yi Chu, Yu Hui Wang, Tzyh Chyuan Hour, Chia Jui Yen, Wen Chang Chang, Ju Ming Wang

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)503-513
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number2
DOIs
Publication statusPublished - Jan 15 2017

Fingerprint

CCAAT-Enhancer-Binding Protein-delta
Paclitaxel
Cisplatin
Urinary Bladder
NSC 74859
Carcinoma
Adenosine Triphosphate
Therapeutics
Combination Drug Therapy
Drug Resistance
Heterografts
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of the EGFR/STAT3/CEBPD Axis reverses cisplatin cross-resistance with paclitaxel in the urothelial carcinoma of the urinary bladder. / Wang, Wei Jan; Li, Chien Feng; Chu, Yu Yi; Wang, Yu Hui; Hour, Tzyh Chyuan; Yen, Chia Jui; Chang, Wen Chang; Wang, Ju Ming.

In: Clinical Cancer Research, Vol. 23, No. 2, 15.01.2017, p. 503-513.

Research output: Contribution to journalArticle

Wang, Wei Jan ; Li, Chien Feng ; Chu, Yu Yi ; Wang, Yu Hui ; Hour, Tzyh Chyuan ; Yen, Chia Jui ; Chang, Wen Chang ; Wang, Ju Ming. / Inhibition of the EGFR/STAT3/CEBPD Axis reverses cisplatin cross-resistance with paclitaxel in the urothelial carcinoma of the urinary bladder. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 2. pp. 503-513.
@article{6fe6769270b34548837036af70eec8a2,
title = "Inhibition of the EGFR/STAT3/CEBPD Axis reverses cisplatin cross-resistance with paclitaxel in the urothelial carcinoma of the urinary bladder",
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.",
author = "Wang, {Wei Jan} and Li, {Chien Feng} and Chu, {Yu Yi} and Wang, {Yu Hui} and Hour, {Tzyh Chyuan} and Yen, {Chia Jui} and Chang, {Wen Chang} and Wang, {Ju Ming}",
year = "2017",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-15-1169",
language = "English",
volume = "23",
pages = "503--513",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Inhibition of the EGFR/STAT3/CEBPD Axis reverses cisplatin cross-resistance with paclitaxel in the urothelial carcinoma of the urinary bladder

AU - Wang, Wei Jan

AU - Li, Chien Feng

AU - Chu, Yu Yi

AU - Wang, Yu Hui

AU - Hour, Tzyh Chyuan

AU - Yen, Chia Jui

AU - Chang, Wen Chang

AU - Wang, Ju Ming

PY - 2017/1/15

Y1 - 2017/1/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85011310958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011310958&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-15-1169

DO - 10.1158/1078-0432.CCR-15-1169

M3 - Article

C2 - 27435393

AN - SCOPUS:85011310958

VL - 23

SP - 503

EP - 513

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -