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Notch pathway inhibition mediated by arsenic trioxide depletes tumor initiating cells in small cell lung cancer

Molecular Biology Reports volume 49, pages 2245–2253 (2022)Cite this article

Abstract

Background

Small cell lung cancer (SCLC) is the most malignant type of lung cancer. We previously reported that arsenic trioxide (As2O3) inhibited tumor initiating cells (TICs) of SCLC in vitro. In the present study, we aimed to identify the above effect in vivo and shed light on its underlying mechanism.

Methods and results

TICs were enriched by culturing human SCLC cell line as sphere cells in specified serum-free medium. The expression of stem cell markers, CD133 and CD44, and the in vivo tumorigenicity of both TICs and their parental cells were examined. To demonstrate the inhibitory effect of As2O3 on TICs, cell proliferation, clone formation and sphere formation assays were performed. CD133 and Notch pathway-related factors were also measured after As2O3 treatment. Xenograft models were established by injecting TICs into nude mice. Mice were treated with As2O3 for 14 days. Afterwards, the tumor volume and the expression of CD133 and Notch1 were evaluated. TICs obtained by the above-mentioned method showed elevated levels of stem cell markers and increased tumorigenicity compared with their parental cells. As2O3 treatment largely inhibited TICs proliferation, sphere formation and clonogenic capacity. As2O3 also reduced the expression of CD133 and down-regulated Notch pathway in TICs. Furthermore, As2O3 potently inhibited tumor growth, decreased the expression of CD133 and down-regulated Notch1 in tumors originating from TICs.

Conclusions

Our data demonstrate that As2O3 has a remarkable inhibitory effect on TICs of SCLC both in vitro and in vivo, and the mechanism might involve the down-regulation of Notch pathway.

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Data availability

All data included in this study are available upon request by contacting the corresponding authors.

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82074065, 81602618 and 81672929).

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Authors and Affiliations

  1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China

    Meng-Hang Yang

  2. Department of Respiratory and Critical Care Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, China

    Bing Li

  3. Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China

    Bing Li

  4. Department of Thoracic Oncology, Cancer Center of the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China

    Ke-Jie Chang

Authors
  1. Meng-Hang Yang
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  2. Bing Li
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Contributions

Yang MH designed the study, interpreted the data, prepared the manuscript and acquired funding for the research. Chang KJ and Li B designed the study, acquired funding for the research, prepared the discussion section and revised the final draft of the manuscript.

Corresponding authors

Correspondence to Bing Li or Ke-Jie Chang.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

The animal experiment was given permission by the Committee on Ethics of Biomedicine, Naval Medical University, also known as Second Military Medical University (Reference Number: 20160218-8160110302). Animal welfare and laboratory procedures were performed strictly according to the Guide for the Care and Use of Laboratory Animals (Ministry of Science and Technology of China).

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Yang, MH., Li, B. & Chang, KJ. Notch pathway inhibition mediated by arsenic trioxide depletes tumor initiating cells in small cell lung cancer. Mol Biol Rep 49, 2245–2253 (2022). https://doi.org/10.1007/s11033-021-07046-w

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  • DOI: https://doi.org/10.1007/s11033-021-07046-w

Keywords

  • Small cell lung cancer
  • Arsenic trioxide
  • Tumor initiating cells
  • Notch