期刊
CANCER LETTERS
卷 354, 期 1, 页码 142-152出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.07.044
关键词
Activating transcription factor 4; Signal transducers and activators of transcription 3; Esophageal squamous cell carcinoma; Multidrug resistance
类别
资金
- National Natural Science Foundation of China [81071401, 81101821, 81101822, 81302067, 81302164]
- Natural Science Foundation of Guangdong Province [10451001002004732, S2011040001277]
- Science and Technology Plan Project of Guangdong Province [2011B031800317, 20130319c]
- Science and Technology Plan Project of Fujian Province [2012J05157]
- Science and Technology Key Project of Guangzhou, China [11C26090521]
Multidrug resistance (MDR) is a major challenge to the clinical treatment of esophageal cancer. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, relatively little is known about the expression and function of ATF4 in esophageal squamous cell carcinoma (ESCC) MDR. In this study, we investigate the potential role and mechanisms of ATF4 in ESCC MDR. We demonstrated that overexpression of ATF4 promotes the MDR phenotype in ESCC cells, while depletion of ATF4 in the MDR ESCC cell line induces drug re-sensitization. We also demonstrated that ATF4 transactivates STAT3 expression by directly binding to the signal transducers and activators of transcription 3 (STAT3) promoter, resulting in MDR in ESCC cells. Significantly, inhibition of STAT3 by small interfering RNA (siRNA) or a selective inhibitor (JSI-124) reintroduces therapeutic sensitivity. In addition, increased Bcl-2, survivin, and MRP1 expression levels were observed in ATF4-overexpressing cells. In conclusion, ATF4 may promote MDR in ESCC cells through the up-regulation of STAT3 expression, and thus is an attractive therapeutic target to combat therapeutic resistance in ESCC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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