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Construction and application of a lung cancer stem cell model: antitumor drug screening and molecular mechanism of the inhibitory effects of sanguinarine

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Tumor Biology

Abstract

Lung cancer is a neoplasm with a 5-year survival rate of less than 15 % and a leading cause of death worldwide, despite recent progress in treatment and diagnostic methods. Lung cancer stem-like cells (CSCs) are pivotal in lung cancer metastasis and drug resistance. This study aimed to develop lung CSCs that stably express stem cell properties through transfection to further screen traditional Chinese herbal compounds. Lung adenocarcinoma stem cells, which include various phenotypic subgroups, are normally characterized by high expression levels of pluripotent stem cell genes, particularly Nanog and OCT4. Plasmids containing Nanog and OCT4 were constructed and transfected into cells, and lung CSCs were identified not only in vitro using RT-PCR, Western blotting, plate cloning, sphere formation, drug resistance, and transwell migration but also in vivo using a nude mouse tumorigenicity assay. Subsequently, sanguinarine, which is derived from the whole leaves of the traditional Chinese medicine celandine, was identified through the high-throughput screening of a small-molecule compound library. Investigation of the molecular mechanisms of the effects of sanguinarine revealed that it significantly inhibited lung CSC proliferation, invasion, and apoptosis, possibly via downregulation of the Wnt/β-catenin signaling pathway. Our results indicate that lung CSCs established by gene transfection may provide a stable and effective method of constructing CSCs to effectively screen potential antitumor drugs. Furthermore, these results suggest that sanguinarine may be a natural antitumor compound that targets lung CSCs, laying a foundation for further clinical study.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation (81473627), Shanghai Natural Science Foundation (14ZR1439000), Bureau-Level Scientific Research Projects of Shanghai Municipal Commission of Health and Family Planning (20124078, 20134016) and Hospital Emerging and Frontier Technology Joint Research Project of Shanghai (SHDC12014127).

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Authors and Affiliations

  1. Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Middle 274 Zhijiang Road, Shanghai, 200071, China

    Jia Yang, Zhihong Fang, Jianchun Wu, Xiaoling Yin, Yuan Fang, Fanchen Zhao & Yan Li

  2. Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai, 201203, China

    Jia Yang & Shiguo Zhu

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  1. Jia Yang
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  2. Zhihong Fang
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  3. Jianchun Wu
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  4. Xiaoling Yin
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  5. Yuan Fang
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  6. Fanchen Zhao
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  7. Shiguo Zhu
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  8. Yan Li
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Correspondence to Shiguo Zhu or Yan Li.

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Yang, J., Fang, Z., Wu, J. et al. Construction and application of a lung cancer stem cell model: antitumor drug screening and molecular mechanism of the inhibitory effects of sanguinarine. Tumor Biol. 37, 13871–13883 (2016). https://doi.org/10.1007/s13277-016-5152-5

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  • DOI: https://doi.org/10.1007/s13277-016-5152-5

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