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

A549 Cells Adenocarcinoma of Lung / drug therapy Animals Cell Line, Tumor Drug Repositioning / methods Epithelial-Mesenchymal Transition / drug effects Humans Kaplan-Meier Estimate Lung Neoplasms / drug therapy Male Matrix Metalloproteinase 12 / genetics Mice, Inbred NOD Mice, SCID Neoplasm Metastasis Penfluridol / pharmacology Proteins / metabolism Proto-Oncogene Proteins c-akt / metabolism RNA Interference Receptors, Urokinase Plasminogen Activator / metabolism Signal Transduction / drug effects Transforming Growth Factor beta / metabolism Urokinase-Type Plasminogen Activator / metabolism Xenograft Model Antitumor Assays / methods
Epithelial–mesenchymal transition Invasion Lung adenocarcinoma Matrix metalloproteinase-12 Migration Penfluridol

Journal

Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938

Informations de publication

Date de publication:
Oct 2021
Historique:
received: 11 11 2020
accepted: 11 06 2021
pubmed: 29 7 2021
medline: 8 2 2022
entrez: 28 7 2021
Statut: ppublish

Résumé

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. 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. 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 SNAl1 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.

Identifiants

DOI: 10.1007/s13402-021-00620-1 PMID: 34319576
pubmed: 34319576
doi: 10.1007/s13402-021-00620-1
pii: 10.1007/s13402-021-00620-1
doi:

Substances chimiques

Proteins 0
Receptors, Urokinase Plasminogen Activator 0
Transforming Growth Factor beta 0
Penfluridol 25TLU22Q8H
Proto-Oncogene Proteins c-akt EC 2.7.11.1
Urokinase-Type Plasminogen Activator EC 3.4.21.73
Matrix Metalloproteinase 12 EC 3.4.24.65

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1087-1103

Subventions

Organisme : Taipei Medical University
ID : 110-eva-14

Informations de copyright

© 2021. Springer Nature Switzerland AG.

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Auteurs

Wen-Yueh Hung (WY)

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

Wei-Jiunn Lee (WJ)

Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Guo-Zhou Cheng (GZ)

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

Ching-Han Tsai (CH)

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

Yi-Chieh Yang (YC)

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 11031, Taipei, Taiwan.
Department of Medical Research, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.

Tsung-Ching Lai (TC)

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

Ji-Qing Chen (JQ)

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 11031, Taipei, Taiwan.
Department of Cancer Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.

Chi-Li Chung (CL)

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.

Jer-Hwa Chang (JH)

Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. m102094030@tmu.edu.tw.
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.
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. m102094030@tmu.edu.tw.
Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. m102094030@tmu.edu.tw.

Ming-Hsien Chien (MH)

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 11031, Taipei, Taiwan. mhchien1976@gmail.com.
Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. mhchien1976@gmail.com.
Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan. mhchien1976@gmail.com.
ORCID: 0000-0002-0084-7231

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Blocking MMP-12-modulated...
questionsmedicales.fr › Tumeurs › Tumeurs par siège › Tumeurs du thorax › Adénocarcinome pulmonaire › Blocking MMP-12-modulated...
questionsmedicales.fr › Eucaryotes › Animaux › Blocking MMP-12-modulated...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Blocking MMP-12-modulated...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Repositionnement des médicaments › Blocking MMP-12-modulated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transdifférenciation cellulaire › Transition épithélio-mésenchymateuse › Blocking MMP-12-modulated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Blocking MMP-12-modulated...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Estimation de Kaplan-Meier › Blocking MMP-12-modulated...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Blocking MMP-12-modulated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Secreted matrix metalloproteinases › Matrix metalloproteinase 12 › Blocking MMP-12-modulated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée NOD › Blocking MMP-12-modulated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris SCID › Blocking MMP-12-modulated...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Métastase tumorale › Blocking MMP-12-modulated...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipéridines › Penfluridol › Blocking MMP-12-modulated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Blocking MMP-12-modulated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-akt › Blocking MMP-12-modulated...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Interférence par ARN › Blocking MMP-12-modulated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs à l'activateur du plasminogène de type urokinase › Blocking MMP-12-modulated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Blocking MMP-12-modulated...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › Blocking MMP-12-modulated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du sang › Activateurs du plasminogène › Activateur du plasminogène de type urokinase › Blocking MMP-12-modulated...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Blocking MMP-12-modulated...