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Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition

Authors
 Hyeon-Ok Jin  ;  Yun-Han Lee  ;  Jin-Ah Park  ;  Jin-Hee Kim  ;  Sung-Eun Hong  ;  Hyun-Ah Kim  ;  Eun-Kyu Kim  ;  Woo Chul Noh  ;  Byung-Hak Kim  ;  Sang-Kyu Ye  ;  Yoon Hwan Chang  ;  Seok-Il Hong  ;  Young-Joon Hong  ;  In-Chul Park  ;  Jin Kyung Lee 
Citation
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol.444(4) : 502-508, 2014 
Journal Title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
ISSN
 0006-291X 
Issue Date
2014
MeSH
Aminosalicylic Acids/pharmacology ; Antineoplastic Agents/pharmacology ; Benzenesulfonates/pharmacology* ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Humans ; Imidazoles/pharmacology* ; Lung/drug effects ; Lung/metabolism ; Lung/pathology ; Lung Neoplasms/drug therapy* ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors* ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Kinase Inhibitors/pharmacology* ; Quinolines/pharmacology* ; RNA Interference ; RNA, Small Interfering/genetics ; STAT3 Transcription Factor/antagonists & inhibitors* ; STAT3 Transcription Factor/genetics ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/antagonists & inhibitors* ; TOR Serine-Threonine Kinases/metabolism
Keywords
Akt ; Bim ; CHOP ; PI3K ; Stat3 ; mTOR
Abstract
The PI3K/Akt/mTOR axis in lung cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for lung cancer. However, non-small cell lung cancer cells are resistant to BEZ235, a dual inhibitor of PI3K and mTOR. Interestingly, blockage of Stat3 with a selective inhibitor, S3I-201, or siRNA dramatically sensitized the BEZ235-induced cell death, as evident from increased PARP cleavage. Furthermore, inhibition of Stat3 led to enhancement of cell death induced by LY294002, a PI3K inhibitor. Treatment of cells with a combination of BEZ235 and S3I-201 significantly induced the proapoptotic transcription factor, CHOP, and its targets, Bim and DR4. Knockdown of CHOP or Bim suppressed cell death stimulated by the combination treatment, implicating the involvement of these BEZ235/S3I-201-induced factors in pronounced cell death. Moreover, the BEZ235/S3I-201 combination enhanced TRAIL-induced cell death. Our results collectively suggest that blockage of Stat3 presents an effective strategy to overcome resistance to PI3K/Akt/mTOR inhibition.
Full Text
http://www.sciencedirect.com/science/article/pii/S0006291X14001107
DOI
10.1016/j.bbrc.2014.01.086
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Lee, Yun Han(이윤한)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/98204
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