Research Papers:

A combination of valproic acid sodium salt, CHIR99021, E-616452, tranylcypromine, and 3-Deazaneplanocin A causes stem cell-like characteristics in cancer cells

Shuang Sha, Yuanfen Zhai, Chengzhao Lin, Heyong Wang, Qing Chang, Shuang Song, Mingqiang Ren and Gentao Liu _

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Oncotarget. 2017; 8:53302-53312. https://doi.org/10.18632/oncotarget.18396

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Shuang Sha1,2, Yuanfen Zhai3, Chengzhao Lin4, Heyong Wang4, Qing Chang2, Shuang Song4, Mingqiang Ren4 and Gentao Liu4,5

1Tongji University School of Life Sciences and Technology, Shanghai, China

2Clinical Research Center, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China

3Department of Immunity, Tongji University School of Medicine, Shanghai, China

4Center for Translational Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

5Center for Cancer Immunotherapy, Shanghai Biomed-Union Biotechnology Co. Ltd, Shanghai International Medical Zone, Shanghai, China

Correspondence to:

Gentao Liu, email: liugt@tongji.edu.cn

Keywords: non-small cell lung cancer, lung cancer stem-like cells, CD133, small molecule compounds, NOTCH signaling

Received: August 15, 2016    Accepted: May 12, 2017    Published: June 07, 2017


Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1. The A549 stem-like cells displayed resistance to the chemotherapeutic drugs etoposide and cisplatin, epithelial-to-mesenchymal transition properties, and increased protein expression levels of NOTCH1 and Hes Family bHLH Transcription Factor 1 (HES1). When A549 cells were pretreated with a NOTCH signaling pathway inhibitor before compound induction, expression of the NOTCH1 target gene HES1 was reduced. This demonstrated that the NOTCH signaling pathway in the putative A549 stem-like cells had been activated. Together, the results of our study showed that a combination of five small molecule agents could transform A549 cells into putative stem-like cells, and that these compounds could also elevate CD133 and ABCG2 protein expression levels in H460 cells. This study provides a convenient method for obtaining lung CSLCs, which may be an effective strategy for developing lung carcinoma treatments.

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