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

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

  • Cell Oncol (Dordr). 2021 Oct;44(5):1087-1103. doi: 10.1007/s13402-021-00620-1.
Wen-Yueh Hung 1,  Wei-Jiunn Lee 2 3,  Guo-Zhou Cheng 1,  Ching-Han Tsai 1,  Yi-Chieh Yang 1 4,  Tsung-Ching Lai 5,  Ji-Qing Chen 1 6,  Chi-Li Chung 7 8,  Jer-Hwa Chang 9 10 11 12,  Ming-Hsien Chien 13 14 15 16
Affiliations

Affiliations

  • 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 11031, Taipei, Taiwan.
  • 2 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 3 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 Department of Medical Research, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
  • 5 Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Hsing Long Road, Section 3, Taipei, 11696, Taiwan.
  • 6 Department of Cancer Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
  • 7 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 8 Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
  • 9 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. m102094030@tmu.edu.tw.
  • 10 Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Hsing Long Road, Section 3, Taipei, 11696, Taiwan. m102094030@tmu.edu.tw.
  • 11 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. m102094030@tmu.edu.tw.
  • 12 Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. m102094030@tmu.edu.tw.
  • 13 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 11031, Taipei, Taiwan. mhchien1976@gmail.com.
  • 14 Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
  • 15 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
  • 16 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan. mhchien1976@gmail.com.
PMID: 34319576 DOI: 10.1007/s13402-021-00620-1
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.

Keywords

Epithelial–mesenchymal transition; Invasion; Lung adenocarcinoma; Matrix metalloproteinase-12; Migration; Penfluridol.

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