標題: Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells
作者: Chiu, Huan-Chih
Chou, Ding-Li
Huang, Chin-Ting
Lin, Wen-Hsing
Lien, Tzu-Wen
Yen, Kuei-Jung
Hsu, John T. -A.
生物科技學系
Department of Biological Science and Technology
關鍵字: RITA;Stat3;WP1066;Doxorubicin sensitivity;Apoptosis
公開日期: 1-Jun-2011
摘要: Epidermal growth factor receptor (EGFR) is a proven therapeutic target to treat a small subset of non small cell lung cancer (NSCLC) harboring activating mutations within the EGFR gene. However, many NSCLC patients are not sensitive to EGFR inhibitors, suggesting that other factors are implicated in survival of NSCLC cells. Signal transducers and activators of transcription 3 (Stat3) function as transcription factor to mediate cell survival and differentiation and the dysregulation of Stat3 has been discovered in a number of cancers. In this study, we found that a small molecule, reactivation of p53 and induction of tumor cell apoptosis (RITA), showed anti-cancer activity against gefitinib-resistant H1650 cells through a p53-independent pathway. Stat3 suppression by RITA attracted our attention to investigate the role of Stat3 in sustaining survival of H1650 cells. Pharmacological and genetic approaches were employed to down-regulate Stat3 in H1650 cells. WP1066, a known Stat3 inhibitor, was shown to exhibit inhibitory effect on the growth of H1650 cells. Meanwhile, apoptosis activation by siRNA-mediated down-regulation of Stat3 in H1650 cells provides more direct evidence for the involvement of Stat3 in viability maintenance of H1650 cells. Moreover, as a novel identified Stat3 inhibitor, RITA increased doxorubicin sensitivity of H1650 cells in vitro and in vivo, suggesting that doxorubicin accompanied with Stat3 inhibitors may be considered as an alternative strategy to treat NSCLC patients who have inherent resistance to doxorubicin. Overall, our observations reveal that targeting Stat3 may be an effective treatment for certain NSCLC cells with oncogenic addition to Stat3. (C) 2011 Elsevier Inc. All rights reserved.
URI: http://dx.doi.org/10.1016/j.bcp.2011.03.003
http://hdl.handle.net/11536/8806
ISSN: 0006-2952
DOI: 10.1016/j.bcp.2011.03.003
期刊: BIOCHEMICAL PHARMACOLOGY
Volume: 81
Issue: 11
起始頁: 1263
結束頁: 1270
Appears in Collections:Articles


Files in This Item:

  1. 000290598200001.pdf