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Rapamycin inhibits lung squamous cell carcinoma growth by downregulating glypican-3/Wnt/β-catenin signaling and autophagy

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

There is not much progress in the treatment for lung squamous cell carcinoma LSCC in the past few years. Rapamycin Rapa, an inhibitor of mammalian target of rapamycin mTOR, has exhibited antitumor efficacy in a variety of malignant tumors. It has recently been reported that Rapamycin can induce autophagy signaling pathway in lung cancer and Glypican-3GPC3 can promote the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling pathway. The aim of this study is to investigate the mechanisms of rapamycin’s antitumor efficacy in relation to GPC3/Wnt/β-catenin pathway and autophagy in LSCC.

Methods

SK-MES-1 cells, a LSCC cell line, were treated with various concentrations of rapamycin with or without Glypican-3 GPC3-targeting siRNA. SK-MES-1 cell proliferation was determined by MTT assay. Protein expression levels of GPC3, β-catenin, Beclin-1 were checked via western blotting. We established the xenograft mice model to investigate the suppression effect of rapamycin on LSCC. In addition, we further testified the metabolism protein of autophagy process using the xenograft tumor tissue.

Results

Rapamycin could inhibit the SK-MES-1 cell proliferation in a concentration-dependent manner both in vitro and in vivo by decreasing the GPC3 expression and downregulating the glypican-3/Wnt/β-catenin signaling pathway. In addition, we found that GPC3 silencing can activate the glypican-3/Wnt/β-catenin pathway and autophagy, which contribute to the suppression of tumor growth both in vitro and in vivo.

Conclusion

Rapamycin suppresses the growth of lung cancer through down-regulating glypican-3/Wnt/β-catenin signaling, which mediates with activation of autophagy. This study suggests GPC3 is a new promising target for rapamycin in the treatment of lung cancer.

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Funding

This work was supported by National Natural Science Foundation of China 81602703, the Natural Science Foundation of Ningbo2018A610382, Zhejiang Medicine and Health Sciences Research Fund 2020379758, 2019 Jiaxing Key Discipline of Medicine—OncologySupporting Subject2019-zc-11.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Zhejiang Province, Ningbo, 315000, China

    Yanyu Bi & Kesang Li

  2. Department of Medical Oncology, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Zhejiang Province, Jiaxing, 314000, China

    Yanyu Bi, Yiming Jiang, Xia Li & Guoxin Hou

  3. Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China

    Kesang Li

  4. Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China

    Kesang Li

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  1. Yanyu Bi
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  2. Yiming Jiang
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  3. Xia Li
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  4. Guoxin Hou
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  5. Kesang Li
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Correspondence to Kesang Li.

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Bi, Y., Jiang, Y., Li, X. et al. Rapamycin inhibits lung squamous cell carcinoma growth by downregulating glypican-3/Wnt/β-catenin signaling and autophagy. J Cancer Res Clin Oncol 147, 499–505 (2021). https://doi.org/10.1007/s00432-020-03422-4

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  • DOI: https://doi.org/10.1007/s00432-020-03422-4

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