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Blocking MMP-12-modulated epithelial-mesenchymal transition by repurposing penfluridol restrains lung adenocarcinoma metastasis via uPA/uPAR/TGF-β/Akt pathway

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Abstract

Purpose

Metastasis of lung adenocarcinoma (LADC) is a crucial factor determining patient survival. Repurposing of the antipsychotic agent penfluridol has been found to be effective in the inhibition of growth of various cancers. As yet, however, the anti-metastatic effect of penfluridol on LADC has rarely been investigated. Herein, we addressed the therapeutic potential of penfluridol on the invasion/metastasis of LADC cells harboring different epidermal growth factor receptor (EGFR) mutation statuses.

Methods

MTS viability, transwell migration and invasion, and tumor endothelium adhesion assays were employed to determine cytotoxic and anti-metastatic effects of penfluridol on LADC cells. Protease array, Western blot, immunohistochemistry (IHC), immunofluorescence (IF) staining, and expression knockdown by shRNA or exogenous overexpression by DNA plasmid transfection were performed to explore the underlying mechanisms, both in vitro and in vivo.

Results

We found that nontoxic concentrations of penfluridol reduced the migration, invasion and adhesion of LADC cells. Protease array screening identified matrix metalloproteinase-12 (MMP-12) as a potential target of penfluridol to modulate the motility and adhesion of LADC cells. In addition, we found that MMP-12 exhibited the most significantly adverse prognostic effect in LADC among 39 cancer types. Mechanistic investigations revealed that penfluridol inhibited the urokinase plasminogen activator (uPA)/uPA receptor/transforming growth factor-β/Akt axis to downregulate MMP-12 expression and, subsequently, reverse MMP-12-induced epithelial–mesenchymal transition (EMT). Subsequent analysis of clinical LADC samples revealed a positive correlation between MMP12 and mesenchymal-related gene expression levels. A lower survival rate was found in LADC patients with a SNAl1high/MMP12high profile compared to those with a SNAl1low/MMP12low profile.

Conclusions

Our results indicate that MMP-12 may serve as a useful biomarker for predicting LADC progression and as a promising penfluridol target for treating metastatic LADC.

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Data availability

All data generated or analyzed during this study are included in this article and its supplemental files.

Abbreviations

BM:

basement membrane

ECM:

extracellular matrix

EMT:

epithelial–mesenchymal transition

GEO:

Gene Expression Omnibus

KM plotter:

Kaplan–Meier plotter

LADC:

lung adenocarcinoma

MMP:

matrix metalloproteinase

NSCLC:

non-small cell lung cancer

SCC:

squamous cell carcinoma

TCGA:

The Cancer Genome Atlas

TGF-β:

transforming growth factor-β

uPA:

urokinase plasminogen activator

uPAR:

uPA receptor

WT:

wild-type

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Acknowledgements

We thank the National RNAi Core Facility, Academia Sinica (Taipei, Taiwan) for providing shRNAs. We also thank Dr. Tsang-Chih Kuo and Dr. Ching-Chow Chen (National Taiwan University, Taipei, Taiwan) for offering the Snail- and Slug-overexpression plasmids and the myr-Akt plasmid, respectively.

Funding

This study was supported by the Taipei Medical University Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan (to M.-H. Chien). This study was also supported by a grant (110-eva-14) from Wan Fang Hospital, Taipei Medical University (to J.-H. Chang).

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Authors and Affiliations

  1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 11031, Taipei, Taiwan

    Wen-Yueh Hung, Guo-Zhou Cheng, Ching-Han Tsai, Yi-Chieh Yang, Ji-Qing Chen & Ming-Hsien Chien

  2. Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Wei-Jiunn Lee & Jer-Hwa Chang

  3. Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Wei-Jiunn Lee

  4. Department of Medical Research, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan

    Yi-Chieh Yang

  5. Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Hsing Long Road, Section 3, Taipei, 11696, Taiwan

    Tsung-Ching Lai & Jer-Hwa Chang

  6. Department of Cancer Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Ji-Qing Chen

  7. School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Chi-Li Chung & Jer-Hwa Chang

  8. Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan

    Chi-Li Chung

  9. Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Jer-Hwa Chang & Ming-Hsien Chien

  10. TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan

    Ming-Hsien Chien

  11. Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan

    Ming-Hsien Chien

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  1. Wen-Yueh Hung
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Contributions

Conceptualization, M-HC, J-HC and W-YH; methodology, W-JL, G-ZC, C-HT, Y-CY, T-CL and J-QC; writing, original draft preparation, M-HC, J-HC and C-LC; writing, review and editing, M-HC and W-YH. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Jer-Hwa Chang or Ming-Hsien Chien.

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All animal experiments were carried out in accordance with guidelines of a protocol approved by the Taipei Medical University Animal Ethics Research Board.

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Hung, WY., Lee, WJ., Cheng, GZ. et al. Blocking MMP-12-modulated epithelial-mesenchymal transition by repurposing penfluridol restrains lung adenocarcinoma metastasis via uPA/uPAR/TGF-β/Akt pathway. Cell Oncol. 44, 1087–1103 (2021). https://doi.org/10.1007/s13402-021-00620-1

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