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

Wen Yueh Hung, Wei Jiunn Lee, Guo Zhou Cheng, Ching Han Tsai, Yi Chieh Yang, Tsung Ching Lai, Ji Qing Chen, Chi Li Chung, Jer Hwa Chang, Ming Hsien Chien

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1087-1103
Number of pages17
JournalCellular Oncology
Volume44
Issue number5
DOIs
Publication statusPublished - Oct 2021

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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